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Abstract Background Despite the progress of advanced target therapeutic agents and immune checkpoint inhibitors, EGFR‐TKI resistance is still one of the biggest obstacles in treating lung cancer. Clinical studies with autophagy inhibitors are actively underway to overcome drug resistance. Methods We used PC9, PC9/GR, and HCC827/GR cell lines to evaluate the activation of autophagy and EGFR‐TKI resistance. Chloroquine was applied as an autophagic blocker and verteporfin was utilized as a YAP inhibitor. Results In this study, we tried to reveal the effect of autophagy adaptor p62 which is accumulated by autophagy inhibitor in EGFR‐TKI‐resistant lung adenocarcinoma. We identified that p62 has oncogenic functions that induce cell proliferation and invasion of EGFR‐TKI‐resistant lung adenocarcinoma. Interestingly, we found for the first time that YAP regulates p62 transcription through ERK, and YAP inhibition can suppress the expression of oncogenic p62. We also confirmed that the expressions of p62 and YAP have a positive correlation in EGFR‐mutant lung adenocarcinoma patients. To block cell survival via perturbing YAP‐p62 axis, we treated EGFR‐TKI‐resistant lung cancer cells with YAP inhibitor verteporfin. Remarkably, verteporfin effectively caused the death of EGFR‐TKI‐resistant lung cancer cells by decreasing the expressions of p62 with oncogenic function, YAP, and its target PD‐L1. So, the cumulative effect of oncogenic p62 should be considered when using autophagy inhibitors, especially drugs that act at the last stage of autophagy such as chloroquine and bafilomycin A1. Conclusion Finally, we suggest that targeting YAP‐p62 signaling axis can be useful to suppress the EGFR‐TKI‐resistant lung cancer. Therefore, drug repurposing of verteporfin for lung cancer treatment may be valuable to consider because it can inhibit critical targets: p62, YAP, and PD‐L1 at the same time.

Abstract Background Acquired epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance limits the long-term clinical efficacy of tyrosine kinase-targeting drugs. Although most of the mechanisms of acquired EGFR-TKI resistance have been revealed, the mechanism of ~ 15% of cases has not yet been elucidated. Methods Cell viability was analysed using the Cell Counting Kit-8 (CCK-8) assay. Proteome profiler array analysis was performed to find proteins contributing to acquired EGFR-TKI resistance. Secreted OPN was detected by ELISA. Immunohistochemical analysis was conducted to detect expression of integrin αV in NSCLC tissue. The effect of VS-6063 on apoptosis and proliferation of PC9 gefitinib-resistant cells was detected by fluorescence-activated cell sorting (FACS) and clonogenic assays. A mouse xenograft model was used to assess the effect of VS-6063 on the sensitivity of PC9 gefitinib-resistant cells to gefitinib. Results OPN was overexpressed in acquired EGFR-TKI-resistant NSCLCs. Secreted OPN contributed to acquired EGFR-TKI resistance by activating the integrin αVβ3/FAK pathway. Inhibition of FAK signalling increased sensitivity to EGFR-TKIs in PC9 gefitinib-resistant cells both in vitro and in vivo. Conclusions OPN contributes to acquired EGFR-TKI resistance by up-regulating expression of integrin αVβ3, which activates the downstream FAK/AKT and ERK signalling pathways to promote cell proliferation in NSCLC.

For cutaneous squamous cell carcinoma (cSCC), topical treatment is an essential option for patients who are not candidates for, or who refuse, surgery. Epidermal growth factor receptor (EGFR) plays a key role in the development of cSCC, but EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, have shown only partial clinical benefit in this disease. Thus, there is an unmet need to develop novel strategies for improving the efficacy of TKIs in cSCC. We previously demonstrated that the tumor-suppressive microRNA (miRNA) miR-634 functions as a negative modulator of the cytoprotective cancer cell survival processes and is a useful anticancer therapeutic agent. In the present study, we found that topical application of an ointment containing miR-634 inhibited in vivo tumor growth without toxicity in a cSCC xenograft mouse model and a 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced papilloma mouse model. Functional validation revealed that miR-634 overexpression reduced glutaminolysis by directly targeting ASCT2, a glutamine transporter. Furthermore, overexpression of miR-634 synergistically enhanced TKI-induced cytotoxicity by triggering severe energetic stress in vitro and in vivo. Thus, we propose that topical treatment with miR-634 ointment is a useful strategy for improving for EGFR TKI-based therapy for cSCC.

Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) protein serve as a critical pillar in the treatment of non-small cell lung cancer (NSCLC), but resistance is universal. Identifying the potential key factors of drug resistance to EGFR-TKIs is essential to treat patients with EGFR mutant lung cancer. Our research here shows that bruceine H suppressed the proliferation, migration, and invasion of lung cancer cells; inhibited the growth of human NSCLC cell xenografts; and enhanced the therapeutic effects of gefitinib in the PC-9/GR xenograft models, possibly by inhibiting Notch3. In order to analyze the potential targets of the combination of Notch3 and EGFR-TKIs on resistance to EGFR, we analyzed the differences of gene expression between NSCLC tissues and EGFR-driven gefitinib-resistant tumoral groups and then identify through the WGCNA key genes that may provide therapeutic targets for TKI-resistant lung cancer xenograft models. We confirmed that EGFR-TKI in combination with Notch3 inhibitor can inhibit the expression of β-catenin and enhance the level of FOXO3a, leading to improved recurrence-free survival and overall survival of the xenotransplantation model. These results support that the combination of gefitinib and bruceine H may provide a promising alternative strategy for treating acquired EGFR-TKI resistance in patients with NSCLC.

Nowadays, lung cancer has the highest mortality worldwide. The emergence of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has greatly improved the survival of patients with non-small cell lung cancer (NSCLC) having EGFR-TKI-sensitive mutations. Unfortunately, acquired resistance happens for most patients. In the present research, we found that EGFR-TKIs (such as gefitinib and osimertinib) can induce autophagy in NSCLC cell lines. Compared with parental sensitive cells, drug-resistant cells have higher autophagy activity. The use of an autophagy inhibitor could enhance the toxicity of gefitinib and osimertinib, which indicates that the enhancement of protective autophagy might be one of the mechanisms of EGFR-TKI resistance in NSCLC. In addition, increased autophagy activity is associated with decreased enhancer of zeste homolog 2 (EZH2) expression. Knockdown of EZH2 or EZH2 inhibitor treatment could lead to increased autophagy in NSCLC cells, indicating that EZH2 is a negative regulator of autophagy. We revealed that the increase in autophagy caused by the reduction of EZH2 was reversed in vitro and in vivo when combining gefitinib or osimertinib with suberoylanilide hydroxamic acid (SAHA), a broad-spectrum histone deacetylase inhibitor (HDACi). In conclusion, our results indicated that the combination of EGFR-TKIs and SAHA may be a new strategy to overcome EGFR-TKIs acquired resistance.

We presented a 67-year-old nonsmoking female lung adenocarcinoma patient with novel epidermal growth factor receptor (EGFR) A289G/F287_G288insHA cis mutations who responded positively to sintilimab combined with regorafenib and albumin paclitaxel, and sequential treatment of icotinib. Gene mutations in patients were detected by next-generation sequencing (NGS) technology, and changes in gene mutations before and after treatments were observed by ctDNA monitoring. We observed the efficacy of the patient through chest computed tomography (CT) imaging and carcinoembryonic antigen (CEA) level and found that the patient benefited from immunotherapy in combination with antiangiogenesis and chemotherapy for more than 1 year, CEA levels initially fell sharply and then rebounded during the treatment period. After changing to EGFR-TKI therapy, the CEA level of the patient does not only decreased sharply at the initial stage of treatment but also rebounded and increased at the later stage of treatment. The patient was tested for genetic mutations after 4 months of sequential EGFR-TKI therapy and was found to have lost all previous EGFR mutations, which may be the cause of resistance to targeted drug icotinib. We believe that our findings have enriched the EGFR mutation spectrum in NSCLC and highlighted the possible choice for patients harboring this mutation by immunotherapy combined with chemotherapy and antivascular therapy, and EGFR-TKI-targeted therapy. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to estimate the efficacy and safety of bevacizumab combined with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in advanced non‐small cell lung cancer (NSCLC) patients. Methods: We searched randomized controlled trials (RCTs) on bevacizumab combined with EGFR TKIs in the NSCLC Cochrane Library, Web of Science, PubMed and Embase. The data were extracted and assessed according to the Cochrane Handbook. We calculated the hazard ratio (HR), risk ratio (RR), and confidence interval (CI), and accomplished this meta‐analysis with Stata 14 software. Results: Of 1301 articles scanned, five articles were involved in this meta‐analysis. We determined that compared with using EGFR TKIs alone, combination treatment significantly prolongs progression‐free survival (PFS) (HR = 0.61, 95% CI = 0.52–0.70; p < 0.001), and increases the objective response rate (ORR) (RR = 1.15, 95% CI: 1.01–1.30, p = 0.10). However, there was no significant difference in overall survival (OS) between the two groups (HR = 0.95, 95% CI = 0.78–1.11; p = <0.001) and combination treatment increases the risks of serious adverse events (SAEs) (RR = 1.58, 95% CI: 1.21–2.05, p = 0.002). Conclusions: Bevacizumab combined with EGFR‐TKI significantly improves PFS and ORR in patients with advanced NSCLC, but there is no substantial difference in OS and increase the risks of serious adverse events. [ABSTRACT FROM AUTHOR]

In epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC), acquired resistance to EGFR tyrosine kinase inhibitors (TKI) leads to disease progression. Strategies to overcome the resistance are required in treatment for advanced lung cancer. In this study, we investigated the therapeutic effect of afatinib and HangAmDan-B1 (HAD-B1) co-administration in gefitinib-resistant NSCLC using HCC827-GR, NSCLC cell line with gefitinib resistance, and the HCC827-GR cell implanted mouse model. HAD-B1 consists of 4 herbs, Panax notoginseng Radix, Cordyceps militaris, Panax ginseng C. A. Mey, and Boswellia carteri Birdwood, and has been reported to be effective in patients with advanced lung cancer in clinical practice. Our findings demonstrated that HAD-B1 combined with afatinib markedly inhibited cell proliferation and induced apoptosis compared to afatinib monotherapy and HAD-B1 monotherapy. Inhibition of HCC827-GR cell proliferation by HAD-B1 occurred through MET amplification and reduced phosphorylation, and the synergistic effect of afatinib and HAD-B1 induced cell cycle arrest and apoptosis in HCC827-GR cells via the downregulation of ERK and mTOR signaling pathways. In hematology and biochemistry tests, HAD-B1 alleviated the toxicity of tumor. In conclusion, HAD-B1 combined with afatinib would be a promising therapeutic strategy for NSCLC with EGFR-TKI resistance. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the efficacy of prophylactic traditional Chinese medicine (TCM) on skin toxicities in patients with advanced lung adenocarcinoma treated with first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in a randomized-controlled trial (RCT). Materials and methods: This pilot study was a prospective, single-center, double-blinded RCT. The study enrolled patients with a new diagnosis of locally advanced and metastatic lung adenocarcinoma harboring EGFR mutations who were treated with first-line afatinib from July 1, 2016 to December 31, 2017. Thirty patients who met the inclusion and exclusion criteria were assigned to the TCM and placebo groups with simple randomization. TCM and placebo were initiated at the same time as afatinib and were administered for 3 months. The survival of each subject was followed until 3 years. Results: There were 36 patients with newly diagnosed lung adenocarcinoma during the study period. After the exclusion of 6 patients, the remaining 30 patients were assigned to the TCM (n = 14) and placebo (n = 16) groups comprising the intention-to-treat population. The time to first skin toxicity was 22.3 days in the TCM group and 17.6 days in the placebo group (P =.510) in the per-protocol population. The analysis of the present pilot study results determined that the difference in time to first skin toxicity between the 2 groups would reach statistical significance with a sample size of 237 based on a power of 0.8. There were significant differences in certain subscales of quality of life between the TCM and placebo groups; however, there was no significant difference in progression-free survival or overall survival between the 2 groups. Conclusions: Integrative TCM may prolong the time to first skin toxicity in patients with advanced lung adenocarcinoma treated with first-line afatinib. Prophylactic TCM could delay skin toxicity of any grade and reduce the incidence of grade 3 skin toxicity. Future large-scale RCTs are warranted to validate these findings. Trial Registration: ClinicalTrials.gov, NCT05204758. Registered on 24 Jan 2022. [ABSTRACT FROM AUTHOR]

Summary: Objectives In EGFR-mutated non-small cell lung cancer (NSCLC) patients, approximately 80–90% of leptomeningeal metastasis (LM) develops after failed initial treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI). However, the efficacy of rechallenging with previously administered EGFR-TKIs in patients with EGFR-mutated NSCLC and the LM that develops following EGFR-TKI treatment failure remains unknown. Materials and methods We retrospectively reviewed medical records of patients with EGFR-mutated NSCLC and LM, from November 2011 to August 2019. The patients were classified according to the LM treatment type: switched to previously unadministered EGFR-TKIs (Switch-TKI) or rechallenge with previously administered EGFR-TKIs (Rechallenge-TKI). Results In total, 50 patients treated with EGFR-TKI after LM diagnosis were included; 35 were treated with Switch-TKI and 15 with Rechallenge-TKI. The median overall survival (OS) from the time of LM diagnosis was 6.2 months in all study patients. According to the treatment type, the median OS from the time of LM diagnosis was 6.9 months in Switch-TKI patients and 4.9 months in Rechallenge-TKI patients. There was no significant difference in the OS between the Switch-TKI and Rechallenge-TKI groups (P = 0.864). Thirty-five patients were treated with erlotinib and 15 with osimertinib; Regardless of the type for EGFR-TKI, there was no significant difference in OS between patients treated with Switch-TKI and those treated with Rechallenge-TKI. Conclusion Rechallenge of previously administered EGFR-TKIs may be a therapeutic option for LM development after EGFR-TKI treatment failure in patients with EGFR-mutated NSCLC, not only switching to previously unadministered EGFR-TKIs. [ABSTRACT FROM AUTHOR]

Objective To explore the relation between the single nucleotide polymorphism of genes in estrogen receptor signaling pathway and the risk of brain metastasis in NSCLC with EGFR mutation. Methods Genomic DNA was extracted from 105 whole blood samples of NSCLC with EGFR mutation. Seven SNPs in ESR1 and ESR2 genes were selected. Subsequently, the genotypes of these seven SNPs in 105 patients were detected. Kaplan-Meier analysis was used to assess the association between genotype and cumulative brain metastasis rate. Multivariate Cox regression analysis was used to analyze the correlation between genotype variants and the occurrence of brain metastasis. Results The GA/AA genotype of ESR1: rs2982685 and AC/CC genotype of ESR2: rs3020443 were associated with high risk of brain metastasis (HR=5.845, 95%CI: 1.979-17.263, P=0.001; HR=5.288, 95%CI: 1.859-15.036, P=0.002). Conclusion Gene mutations in the estrogen receptor signaling pathway can predict the risk of brain metastases in NSCLC patients with EGFR mutations.

Abstract Background Osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), can be used as second-line treatment for lung cancer patients harboring the T790M substitution. Although osimertinib is more effective than the first-generation EGFR-TKIs used for first-line treatment, its efficacy with respect to long-term patient survival remains unclear even upon the administration of a complete sequence of EGFR-TKI therapy. Moreover, limited information is available regarding genetic diagnostic approaches after the treatment of EGFR-TKI–naïve patients. This study investigated the clinical characteristics of EGFR-mutated lung cancer patients harboring the T790M substitution resistant to EGFR-TKIs, as well as the advantages of rebiopsy and liquid biopsy for these patients. Methods The medical records of patients screened for EGFR mutations were reviewed. Upon failure of naïve treatment with EGFR-TKIs, except for osimertinib, single-plexus cobas version 2 was repeatedly used to detect the T790M substitution in EGFR via tissue or liquid biopsy. Results From April 2016 through May 2019, 113 patients were found to harbor EGFR mutations. Sixty patients were treated with EGFR-TKIs, among whom 46 underwent tissue or liquid biopsy. Twenty-nine of these 46 (63%) patients harbored the T790M substitution. In total, 141 rebiopsies were performed. The T790M substitution was detected in 24 of 43 tissue biopsies and 11 of 98 liquid biopsies. If patients displayed an EGFR exon 19 deletion, had a new lesion, and were administered gefitinib as first-line therapy, they were suspected to harbor the T790M substitution. Furthermore, the T790M substitution was detected through rebiopsy in patients with coexisting original mutations, brain metastases, tumor enlargement by ≥12 mm, or metastases at minor sites. Conclusion Among patients with positive factors associated with the T790M mutation, repeated tissue or liquid biopsies are useful to maximize the detection rate of the T790M substitution. Furthermore, these biopsies need to be repeated numerous times in order to reduce “detection overlook” among such patients.

Background Lung cancer is the leading cause of cancer‐related deaths. Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) are effective for advanced non‐small cell lung cancer (NSCLC) harboring EGFR mutations, some patients experience little or no response. The Glasgow prognostic score (GPS) is an inflammation‐related score based on C‐reactive protein (CRP) and albumin concentrations, and has prognostic value in various cancer settings. This study aimed to evaluate whether GPS could predict response of NSCLC to EGFR‐TKIs. Methods This retrospective multicenter study evaluated patients with NSCLC harboring EGFR mutations who received EGFR‐TKI monotherapy from October 2006 to December 2016. GPS values were determined using CRP and albumin concentrations from before initiation of EGFR‐TKIs. The Kaplan‐Meier method and Cox proportional hazard models were used to evaluate progression‐free survival (PFS) and overall survival (OS). Results In 214 patients, 141, 43, and two patients had GPS values of 0, 1, and 2, respectively. The GPS independently predicted the efficacy of EGFR‐TKIs; good GPS (0–1) conferred significantly better PFS (hazard ratio [HR]: 0.59, 95% confidence interval [CI]: 0.38–0.96, P = 0.03) and OS (HR: 0.56, 95% CI: 0.33–0.96, P = 0.03). Multivariate analysis confirmed that a good GPS (0–1) independently predicted good PFS and OS among patients who had PS of 0–1. Good GPS (0–1) independently predicted good OS among patients receiving treatment in first‐line settings. Conclusions The GPS independently predicted the efficacy of EGFR‐TKIs for EGFR‐mutated NSCLC; however, further studies are needed to validate our findings. Key points Significant findings of the study Glasgow prognostic score (GPS) independently predicted the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) treatment for EGFR‐mutated NSCLC. What this study adds The findings presented in this paper will help to identify patients who will be expected to experience limited or no response to EGFR‐TKI treatment by using GPS.

Background Although many studies have defined mechanisms of resistance to EGFR‐TKIs, acquired resistance remains the major limitation of monotherapy with EGFR‐TKIs. Methods Cell viability was analyzed using a Cell Counting Kit‐8 (CCK‐8) assay. EGFR T790M mutation was sequenced on a HiSeq 4000 platform. mRNAs from HCC827 and HCC827 gefitinib‐resistant (GR) cells were analyzed by genome analyzer‐based deep sequencing. The effect of anlotinib on apoptosis and cell cycle arrest of HCC827 GR was detected by fluorescence‐activated cell sorting (FACS) analysis. A mouse xenograft model was used to assess the effect of anlotinib on HCC827 GR cells. Results The T790M mutation was found in the PC‐9 GR cell line but not in the HCC827 GR cell line. Anlotinib could suppress the growth of HCC827 GR cells by inhibiting FGFR1 in vitro and in a mouse xenograft model. Moreover, FGFR1 was overexpressed in HCC827 GR cells, and the knockdown of FGFR1 reversed gefitinib resistance in HCC827 GR cells. Furthermore, anlotinib induced apoptosis and cell cycle arrest in HCC827 GR cells by increasing the activity of Caspase‐3. Conclusions FGFR1 overexpression could be the mechanism of EGFR‐TKI acquired resistance and anlotinib can suppresse the growth of EGFR‐TKI‐resistant NSCLC cells without T790M mutation.

Abstract Background Calpain 1 (CAPN1) has been found to be a promoter of cancer progression. PTPN1 as a physiological target molecule of CAPN1 plays a dephosphorylated role on multiple receptor tyrosine kinases. This study aimed to reveal the effects of CAPN1/PTPN1 on malignant phenotype and EGFR‐TKI resistance of lung adenocarcinoma (LUAD) cells. Methods A total of 84 primary LUAD tissues and paired paracancerous normal tissues were collected. Quantitative real‐time PCR (qRT‐PCR) and immunohistochemical (IHC) methods were used to measure the expression of CAPN1 and PTPN1 in tissues. qRT‐PCR and western blot were used to detect the expressions of CAPN1, PTPN1, c‐Met and PIK3R2 in cell lines. Cell counting kit‐8 (CCK‐8), colony formation and transwell assay were carried out to evaluate cell erlotinib resistance, proliferation, migration and invasion. Co‐IP assay was used to verify the interaction between proteins. Cycloheximide (CHX) was applied to block protein synthesis. Results CAPN1, c‐Met and PIK3R2 were significantly upregulated and the correlation was positive in LUAD, while PTPN1 was decreased. EGFR‐sensitive mutation was related to CAPN1/PTPN1. in vitro studies showed that PTPN1 can mediate dephosphorylation of c‐Met and PIK3R2 by binding with both, thereby weakening cell proliferation, metastasis and erlotinib resistance, while CAPN1 could enhance the degradation of PTPN1 protein as a cancer promoter. Conclusions CAPN1 enhances the malignant behavior and erlotinib resistance of LUAD cells via degrading PTPN1 and then activating c‐Met/PIK3R2, which suggests CAPN1/PTPN1 may serve as tumor markers or potential targets for diagnosis and treatment of LUAD. Key points Significant findings of the study Superior CAPN1 and inferior PTPN1 were related to activation of c‐Met/PIK3R2 in lung adenocarcinoma. Moreover, regulations of CAPN1 and PTPN1 induced the changes of malignant behavior and erlotinib resistance. What this study adds Our findings confirmed that CAPN1/PTPN1 play crucial roles on proliferation, metastasis and erlotinib resistance of LUAD cells as c‐Met/PIK3R2 regulators, and validated the regulatory mechanism of CAPN1 on PTPN1 in tumor model for the first time.

Objective To investigate the expression of ARL4C in NSCLC and its correlation with clinicopathological features, as well as its role in EGFR-TKI resistance. Methods We collected the tumor and adjacent tissues of 63 NSCLC patients. The mRNA expression of ARL4C was detected by qRT-PCR and the relation between ARL4C and clinicopathological features was analyzed. The expressions of ARL4C in TKI-resistant cell line, control cell line and ARL4C overexpressing cell line were assessed by qRT-PCR and Western blot. The changes of cell activity and IC50 were detected by MTS. Transwell invasion assay was used to detect the effect of ARL4C expression on cell invasion. Results The expression level of ARL4C in NSCLC tissues was lower than that in adjacent tissues (P < 0.05). The expression of ARL4C in NSCLC was closely related to lymph node metastasis, TNM stage and pulmonary membrane invasion (P < 0.05). Compared with control cell line HCC827, the expression levels of ARL4C mRNA and protein in TKI-resistant cell line HCC827/ER and the IC50 of ARL4C overexpressing TKI-resistant cell line HCC827/ER/ARL4C-OE were significantly lower (P < 0.05). Transwell assay results showed that the overexpression of ARL4C inhibited the invasion of lung cancer cell line (P < 0.05). Conclusion The abnormal expression of ARL4C is closely related to lymph node metastasis, TNM stage and pulmonary membrane invasion of NSCLC. Overexpression of ARL4C may improve the sensitivity of NSCLC cells to EGFR-TKI and inhibit the invasion of NSCLC cells.

Osimertinib, a third‐generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI), provides marked clinical benefit for patients with EGFR‐activating mutations. Unfortunately, limited treatments exist for patients who acquire osimertinib resistance. We observed two ‘special’ patients who regained an antitumor response with osimertinib plus aspirin treatment. As previous data indicate that aspirin induces antiproliferative effects in tumor cells, we designed a preclinical study to explore whether aspirin combined with osimertinib could synergistically sensitize osimertinib‐resistant non‐small‐cell lung cancer (NSCLC) cells. The effects of combined treatment with osimertinib and aspirin on osimertinib‐resistant NSCLC cell lines were examined in vitro and in vivo. The combination of osimertinib and aspirin induced strong antiproliferative and proapoptotic effects in osimertinib‐resistant NSCLC cells through inhibition of Akt/FoxO3a signaling component phosphorylation and increased Bim expression. Furthermore, Bim knockdown by siRNA significantly attenuated osimertinib resensitization by aspirin. In vivo, combination of aspirin and osimertinib significantly decreased tumor growth of PC‐9GROR cell xenografts. Data of patients with NSCLC who received osimertinib treatment at Daping Hospital between January 2015 and January 2019 were reviewed retrospectively. According to clinical data for 45 patients with NSCLC, retrospective analysis showed that the median progression‐free survival was significantly longer in the osimertinib plus aspirin group than in the osimertinib group. In summary, aspirin synergistically enhances the antitumor activity of osimertinib in osimertinib‐resistant lung cancer cells through promoting Bim‐dependent apoptosis. This combination therapy may be effective in overcoming acquired resistance to osimertinib and prolonging survival in patients with NSCLC.

Abstract Background The resistance of lung cancer to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is one of the unconquered frontiers in chemotherapy. Mitogen-inducible gene 6 (Mig-6) is known to inhibit the kinase activity of epidermal growth factor receptor (EGFR). Similarly, numerous studies of mouse models suggested tumor suppressive function of Mig-6 in lung cancer. On the contrary, the results of clinical investigations revealed that lung cancer patients with elevated expression of Mig-6 are associated with a poor prognosis. More recent work showed that unlike wild type (WT) EGFR, mutant EGFR phosphorylates Mig-6 and phosphorylated Mig-6 negatively regulates the degradation of EGFR mutants in lung adenocarcinoma. Here, we tried to untangle the controversies surrounding Mig-6 function as a protagonist or an antagonist of EGFR-TKI resistant lung cancer. Methods We compared the expression and phosphorylation status of Mig-6 in the EGFR-TKI resistant lung adenocarcinoma (PC9/GR cells) to EGFR-TKI sensitive lung adenocarcinoma (PC9 cells). We investigated the function of Mig-6 by either depletion or overexpression of Mig-6 in those cells and evaluated the efficacy of combining of Mig-6 knock-down and EGFR-TKI treatment in PC9/GR. The correlation between Mig-6 expressions and the prognoses of lung adenocarcinoma was examined by The Cancer Genome Atlas (TCGA) data and clinical samples. Results Our results indicated that the expression of Mig-6 was significantly increased in PC9/GR cells compared to that of PC9 cells. The significant portion of Mig-6 existed as a phosphorylated form in PC9 and PC9/GR cells. Moreover, overexpression of Mig-6 significantly increased the cell proliferation, invasion and epithelial mesenchymal transition (EMT) in PC9 cells. Combination of Mig-6 knock-down and EGFR-TKI treatment significantly overcame the EGFR-TKI resistance of PC9/GR cells. In addition, our analyses of clinical samples confirmed that high Mig-6 expressions positively correlate with a poor prognosis and EGFR-TKI resistance in lung adenocarcinoma. Conclusion Our findings reinforce scientific notion of Mig-6 as an oncoprotein in the context of EGFR-TKI resistant lung adenocarcinoma. We propose that targeting Mig-6 may be a promising strategy to overcome the EGFR-TKI resistance in lung cancer.

While treating cancer, epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) still faces inevitable drug resistance. Investigations into the mechanisms which foster resistance to EGFR-TKI has led to the discovery of novel biomarkers and drug targets, and in turn has enabled the development of third-generation TKIs and proposals for rational therapeutic combinations. The threonine-to-methionine substitution mutation at position 790 (T790M) is clinically validated to engender refractoriness to first- and second-generation TKI, and is a standard-of-care predictive biomarker used in therapeutic stratification. For patients who are T790M-negative, cytotoxic chemotherapy or protracted EGFR-TKI treatment are acceptable treatment standards after disease progression, although combinations of targeted therapies and checkpoint blockade immunotherapy may offer promising alternatives in the future. Among T790M-positive patients, the third-generation EGFR-TKI, osimertinib, has shown superiority over both platinum-doublet chemotherapy and first-generation EGFR-TKI in randomized clinical trials. This article appraises the key literature on the contemporary management of non-small cell lung cancer patients with acquired resistance to EGFR-TKIs, and envisions future directions in translational and clinical research.

Abstract Background The objective of this study was to investigate real-world EGFR mutation testing in patients with metastatic non-small cell lung cancer (NSCLC) upon progression on first−/second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI), and subsequent treatments received. Methods Flatiron Health electronic health records-derived database was used to identify adult patients with metastatic NSCLC treated with first−/second-generation EGFR-TKI from 11/2015–09/2017, with start of first EGFR-TKI defined as the index date. Patients were stratified by receipt of EGFR-TKI as first-line (1 L) or later-line (2 L+) treatment. Mutation testing and subsequent therapies following first−/second-generation EGFR-TKI were described. Results Overall, 782 patients (1 L = 435; 2 L+ =347) were included. Median age was 69.0 years, 63.6% were female, 56.3% were white, 87.1% were treated in community-based practices, and 30.1% of patients died during the study period; median follow-up was 309.0 days. Among the 294 (1 L = 160; 2L+ =134) patients who received subsequent therapies, treatments included chemotherapy only (1 L = 15.6%; 2L+ =21.6%), immunotherapy only (1 L = 13.8%; 2 L+ =41.0%), and targeted therapies (1 L = 70.0%; 2 L+ =36.6%). Specifically, 40 (25.0%) 1 L patients and 7 (5.2%) 2 L+ patients received osimertinib as subsequent therapy. Before the start of subsequent therapy, EGFR T790M resistance mutation testing was performed in 88 (29.9%) patients (1 L = 63 [39.4%]; 2 L+ =25 [18.7%]). Of these patients, 25 (28.4%) were T790M positive, among whom 24 (96.0%) received osimertinib. Conclusions A third of patients received subsequent therapies on disease progression; only 30% of these were tested for EGFR-TKI resistance mutation, prior to receiving subsequent therapies. These results highlight the importance of choosing treatments in the 1 L setting that optimize benefits for patients with EGFR-mutated NSCLC.

Abstract Background Cancer metastasis and drug resistance have traditionally been studied separately, though these two lethal pathological phenomena almost always occur concurrently. Brain metastasis occurs in a large proportion of lung cancer patients (~ 30%). Once diagnosed, patients have a poor prognosis surviving typically less than 1 year due to lack of treatment efficacy. Methods Human metastatic lung cancer cells (PC-9-Br) were injected into the left cardiac ventricle of female athymic nude mice. Brain lesions were allowed to grow for 21 days, animals were then randomized into treatment groups and treated until presentation of neurological symptoms or when moribund. Prior to tissue collection mice were injected with Oregon Green and 14C-Aminoisobutyric acid followed by an indocyanine green vascular washout. Tracer accumulation was determined by quantitative fluorescent microscopy and quantitative autoradiography. Survival was tracked and tumor burden was monitored via bioluminescent imaging. Extent of mutation differences and acquired resistance was measured in-vitro through half-maximal inhibitory assays and qRT-PCR analysis. Results A PC-9 brain seeking line (PC-9-Br) was established. Mice inoculated with PC-9-Br resulted in a decreased survival time compared with mice inoculated with parental PC-9. Non-targeted chemotherapy with cisplatin and etoposide (51.5 days) significantly prolonged survival of PC-9-Br brain metastases in mice compared to vehicle control (42 days) or cisplatin and pemetrexed (45 days). Further in-vivo imaging showed greater tumor vasculature in mice treated with cisplatin and etoposide compared to non-tumor regions, which was not observed in mice treated with vehicle or cisplatin and pemetrexed. More importantly, PC-9-Br showed significant resistance to gefitinib by in-vitro MTT assays (IC50 > 2.5 μM at 48 h and 0.1 μM at 72 h) compared with parental PC-9 (IC50: 0.75 μM at 48 h and 0.027 μM at 72 h). Further studies on the molecular mechanisms of gefitinib resistance revealed that EGFR and phospho-EGFR were significantly decreased in PC-9-Br compared with PC-9. Expression of E-cadherin and vimentin did not show EMT in PC-9-Br compared with parental PC-9, and PC-9-Br had neither a T790M mutation nor amplifications of MET and HER2 compared with parental PC-9. Conclusion Our study demonstrated that brain metastases of lung cancer cells may independently prompt drug resistance without drug treatment.

Abstract Background We investigated the risk factors for leptomeningeal carcinomatosis (LMC) and compared clinical efficacies of various treatment modalities including intrathecal (IT) chemotherapy in patients with lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutations. Methods Using clinical research data from the Asan Medical Center, we retrospectively analyzed data of patients diagnosed with LMC, confirmed via cerebrospinal fluid (CSF) analysis from January 2008 to December 2017. Results We identified 1189 patients with lung adenocarcinoma harboring EGFR mutations. Among these, 9.8% had a median duration of 13.5 (interquartile range [IQR] 6.8–23.6) months from the initial lung cancer diagnosis to LMC occurrence. Younger age (hazard ratio [HR] 1.043, P

Abstract Background Osimertinib (AZD9291) is a third‐generation EGFR‐tyrosine kinase inhibitor (TKI) that selectively inhibits the activating EGFR mutation and T790M mutation, and is currently used globally to treat EGFR‐mutant non‐small cell lung cancer (NSCLC). However, acquired resistance to osimertinib is inevitable. Methods We established osimertinib‐resistant cells (PC9/T790M/AZDR and H1975/AZDR) derived from EGFR‐mutant NSCLC cells harboring T790M mutation, and investigated the mechanism of acquired resistance to osimertinib by whole‐exome sequencing and multiple phospho‐receptor tyrosine kinase (RTK) array. A tumor specimen from an EGFR‐mutant NSCLC patient with acquired resistance to osimertinib was also subjected to immunohistochemical analysis. Results Whole‐exome sequencing analysis demonstrated that genetic alterations, such as acquisition of EGFR C797S, loss of T790M mutation, MET amplification, or mutated KRAS, MEK, BRAF, PIK3CA, were not detected. Analysis of phospho‐RTK array revealed that insulin‐like growth factor‐1 receptor (IGF1R) was activated in PC9/T790M/AZDR and H1975/AZDR cells. Knockdown of IGF1R by siRNA as well as inhibition of IGF1R activation by linstinib (IGF1R inhibitor) significantly restored the sensitivity to osimertinib. Immunohistochemical analysis revealed that the expression level of phosphorylated IGF1R was higher in the tumor specimen from the EGFR‐mutant NSCLC patient with acquired resistance to osimertinib than in the specimen collected prior to the treatment. Conclusions IGF1R activation could occur following treatment with osimertinib in EGFR‐mutant NSCLC with T790M mutation, and might be one of the mechanisms underlying osimertinib resistance. Combined treatment of osimertinib and IGF1R inhibitor might be effective in overcoming the acquired resistance to osimertinib induced by IGF1R activation. Key points Significant findings of the study: Using osimertinib‐resistant cells, we found that IGF1R activation induced by osimertinib treatment in EGFR‐mutant NSCLC with T790M mutation is involved in resistance. Increased phosphorylation of IGF1R was observed in the tumor specimen from an EGFR‐mutant NSCLC patient with acquired osimertinib resistance. What this study adds: IGF1R activation might be one of the mechanisms of osimertinib resistance. A combination therapy with osimertinib and an IGF1R inhibitor might be an optimal approach for overcoming the acquired resistance to osimertinib induced by IGF1R activation.

We presented a 67-year-old nonsmoking female lung adenocarcinoma patient with novel epidermal growth factor receptor (EGFR) A289G/F287_G288insHA cis mutations who responded positively to sintilimab combined with regorafenib and albumin paclitaxel, and sequential treatment of icotinib. Gene mutations in patients were detected by next-generation sequencing (NGS) technology, and changes in gene mutations before and after treatments were observed by ctDNA monitoring. We observed the efficacy of the patient through chest computed tomography (CT) imaging and carcinoembryonic antigen (CEA) level and found that the patient benefited from immunotherapy in combination with antiangiogenesis and chemotherapy for more than 1 year, CEA levels initially fell sharply and then rebounded during the treatment period. After changing to EGFR-TKI therapy, the CEA level of the patient does not only decreased sharply at the initial stage of treatment but also rebounded and increased at the later stage of treatment. The patient was tested for genetic mutations after 4 months of sequential EGFR-TKI therapy and was found to have lost all previous EGFR mutations, which may be the cause of resistance to targeted drug icotinib. We believe that our findings have enriched the EGFR mutation spectrum in NSCLC and highlighted the possible choice for patients harboring this mutation by immunotherapy combined with chemotherapy and antivascular therapy, and EGFR-TKI-targeted therapy.

Introduction of EGFR-TKI has changed the treatment paradigm for NSCLC patient with activating mutations of EGFR exons 18–21, replacing chemotherapy as standard first line treatment. Given the delays in molecular study results we sometimes face the need to start treatment in very symptomatic patients with high tumor burden. The reason for this retrospective study is to analyze the survival impact of performing an induction cytotoxic therapy until obtaining the molecular profile (EGFR mutation), followed by targeted therapy.This is a retrospective analysis of 31 patients who did upfront chemotherapy (ChT) before switching to EGFR TKI upon the molecular profile result. The calculated survival endpoints were progression-free survival (PFS), duration of TKI response and overall survival (OS).All patients were treated with upfront chemotherapy with a median of one cycle (range 1–3) followed by a first generation EGFR-TKI. Median PFS was 13 months (95% CI, 6.6–19.4) and median OS 33 months (95% CI, 11.9–54.0). After first line progression 14 patients were treated with Osimertinib. In this subgroup median OS was 52 months (95% CI, 34.0–69.9). In the multivariable Cox model, only body mass index retained independent prognostic significance for progression-free survival (p = 0.045).Survival outcomes in this cohort are in line with published data regarding first generation EGFR-TKI, both in terms of PFS and OS. Despite the limitations of this study, starting with upfront chemotherapy doesn't seem detrimental in terms of survival outcomes, with the potential advantage of symptomatic control. To our knowledge, this is the first study to address this strategy, which requires further confirmation.

This is a long-term follow-up case report of a 71-year-old man with lung adenocarcinoma and choroidal metastasis harboring an epidermal growth factor receptor mutation. Blurry vision, caused by the choroidal metastasis, improved with first-line treatment with afatinib. Thereafter, osimertinib was administered as a second-line treatment, then chemotherapy containing pemetrexed plus bevacizumab as a third-line treatment. For 61 months, recurrence of choroidal metastasis was absent. Only a few reports of lung cancer with choroidal metastasis provide long-term follow-up of more than five years. Therefore, the clinical course of this patient may provide some insights for long-term management in such cases., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Nakashima et al.)

Background: Treatment of advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has a higher response rate than with conventional chemotherapy in patients positive for EGFR mutations. However, the efficacy of EGFR-TKI therapy may be reduced in patients positive for the EGFR exon 21 L858R point mutation., Objective: To determine the clinical characteristics of patients with EGFR exon 21 L858R point mutation-positive NSCLC who are non-responders to EGFR-TKI therapy and the factors that predict response to EGFR-TKI therapy., Methods: Patients with NSCLC treated with EGFR-TKIs were evaluated for response after treatment, and those who responded were compared with those who did not respond., Results: Of 31 patients, 21 (67.7%) responded to EGFR-TKI therapy (the response group). There were significantly more programmed death ligand 1 (PDL1)-negative patients in the response group than in the non-response group. A significantly higher number of patients in the PDL1-positive group developed interstitial lung disease (ILD) after EGFR-TKI therapy than those in the PDL1-negative group., Conclusion: EGFR-TKI therapy is likely to be non-responsive in PDL1-positive patients with EGFR exon 21 L858R point mutation-positive NSCLC. The PDL1-positive group is at a high risk of developing ILD., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Review Board of Kanazawa Medical University issued approval C057. This study was approved by the Institutional Review Board of Kanazawa Medical University (approval number: C057). Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Takahara et al.)

A 71-year-old woman was treated with osimertinib for stage IV adenocarcinoma with epidermal growth factor receptor (EGFR) mutations. Treatment led to improvements in the primary tumor, multiple lung metastases, and multiple bone metastases. However, nine months later, she presented with marked liver dysfunction and jaundice. Chest and abdominal computed tomography did not show abnormal findings in the liver parenchyma or biliary system. However, blood tests were positive for hepatitis B surface antigen and hepatitis B virus DNA, suggesting hepatitis B virus reactivation. The patient died of liver failure despite treatment with steroids and antiviral drugs.

Introduction: For epidermal growth factor receptor mutation-positive (EGFRm) non-small-cell lung cancer (NSCLC), EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are the preferred first-line (1 L) treatment in the advanced setting. Osimertinib, a third-generation EGFR-TKI, received full approval in 2017 for second-line (2 L) treatment of EGFR T790M-positive NSCLC. The REFLECT study characterizes real-world treatment/testing patterns, attrition rates, and outcomes in patients with EGFRm advanced NSCLC treated with 1 L first-/second-generation (1G/2G) EGFR-TKIs before 1 L osimertinib approval. Methods: Retrospective chart review (NCT04031898) of European/Israeli adults with EGFRm unresectable locally advanced/metastatic NSCLC, initiating 1 L 1G/2G EGFR-TKIs 01/01/15–30/06/18 (index date). Results: In 896 patients (median follow-up of 21.5 months), the most frequently initiated 1 L EGFR-TKI was afatinib (45%). Disease progression was reported in 81%, including 10% (86/896) who died at 1 L. By the end of study, most patients discontinued 1 L (85%), of whom 33% did not receive 2 L therapy. From index, median 1 L real-world progression-free survival was 13.0 (95% confidence interval (CI): 12.3–14.1) months; median overall survival (OS) was 26.2 (95% CI: 23.6–28.4) months. 71% of patients with 1 L progression were tested for T790M; 58% were positive. Of those with T790M, 95% received osimertinib in 2 L or later. Central nervous system (CNS) metastases were recorded in 22% at index, and 15% developed CNS metastases during treatment (median time from index 13.5 months). Median OS was 19.4 months (95% CI: 17.1–22.1) in patients with CNS metastases at index, 24.8 months (95% CIs not available) with CNS metastases diagnosed during treatment, and 30.3 months (95% CI: 27.1, 33.8) with no CNS metastases recorded. Conclusion: REFLECT is a large real-world study describing treatment patterns prior to 1 L osimertinib availability for EGFRm advanced NSCLC. Given the attrition rates highlighted in the study and the impact of CNS progression on outcomes, offering a 1 L EGFR-TKI with CNS penetration may improve patient outcomes in this treatment setting. [ABSTRACT FROM AUTHOR]

Background: Local ablative therapy (LAT) may be beneficial for patients with epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) with oligo-residual disease after treatment with EGFR tyrosine kinase inhibitor (EGFR-TKI). However, this has not been fully established. This study aimed to evaluate the predominant progressive disease (PD) pattern limited to residual sites of disease after treatment with EGFR-TKI.Methods: Patients with advanced EGFR-mutated NSCLC treated with EGFR-TKIs as first-line therapy were retrospectively analysed during a 7-year period. Oligo-residual disease was defined as the presence of 1 - 4 lesions (including the primary site) at 3 months from the start of EGFR-TKI treatment. The predictive factors of PD patterns after EGFR-TKI treatment were evaluated.Results: A total of 207 patients were included. Three months after the start of EGFR-TKI treatment, 66 patients (32%) had oligo-residual disease. A total of 191 patients had PD, 60 with oligo-residual disease and 131 with non-oligo-residual disease. Regarding the pattern, 44 patients (73%) with oligo-residual disease and 37 patients (28%) with non-oligo-residual disease had PD limited to the residual sites. Multivariate logistic regression analysis at 3 months from the start of EGFR-TKI treatment revealed that oligo-residual disease (P < 0.001), the lack of residual central nervous system metastases (P = 0.032), and initial treatment with osimertinib (P = 0.028) were independent predictors of PD limited to residual disease sites.Conclusions: This study provided a rationale for LAT to all sites of residual disease in patients with oligo-residual disease during EGFR-TKI treatment. [ABSTRACT FROM AUTHOR]

Background: Tyrosine kinase inhibitors that act against epidermal growth factor receptor (EGFR) show strong efficacy against non-small cell lung cancer (NSCLC) involving mutated EGFRs. However, most such patients eventually develop resistance to EGFR-TKIs. Numerous researches have reported that messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs) may be involved in EGFR-TKI resistance, but the comprehensive expression profile and competitive endogenous RNA (ceRNA) regulatory network between mRNAs and ncRNAs in EGFR-TKI resistance of NSCLC are incompletely known. We aimed to define a ceRNA regulatory network linking mRNAs and non-coding RNAs that may mediate this resistance. Methods: Using datasets GSE83666, GSE75309 and GSE103352 from the Gene Expression Omnibus, we identified long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and mRNAs differentially expressed between NSCLC cells that were sensitive or resistant to EGFR-TKIs. The potential biological functions of the corresponding differentially expressed genes were analyzed based KEGG pathways. We combined interactions among lncRNAs, miRNAs and mRNAs in the RNAInter database with KEGG pathways to generate transcriptional regulatory ceRNA networks associated with NSCLC resistance to EGFR-TKIs. Kaplan-Meier analysis was used to assess the ability of core ceRNA regulatory sub-networks to predict the progression-free interval and overall survival of NSCLC. The expression of two core ceRNA regulatory sub-networks in NSCLC was validated by quantitative real-time PCR. Results: We identified 8,989 lncRNAs, 1,083 miRNAs and 3,191 mRNAs that were differentially expressed between patients who were sensitive or resistant to the inhibitors. These DEGs were linked to 968 biological processes and 31 KEGG pathways. Pearson analysis of correlations among the DEGs of lncRNAs, miRNAs and mRNAs identified 12 core ceRNA regulatory sub-networks associated with resistance to EGFR-TKIs. The two lncRNAs ABTB1 and NPTN with the hsa-miR-150–5p and mRNA SERPINE1 were significantly associated with resistance to EGFR-TKIs and survival in NSCLC. These lncRNAs and the miRNA were found to be down-regulated, and the mRNA up-regulated, in a resistant NSCLC cell line relative to the corresponding sensitive cells. Conclusion: In this study, we provide new insights into the pathogenesis of NSCLC and the emergence of resistance to EGFR-TKIs, based on a lncRNA-miRNA-mRNA network. [ABSTRACT FROM AUTHOR]

Background: Acquired resistance development is a major challenge in the epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR–TKI) treatment of non–small cell lung cancer (NSCLC). Here, we investigated the potential effects of the concurrent use of anlotinib and EGFR‐TKI to overcome acquired resistance. Methods: We conducted a preclinical study to evaluate the antitumor effects of gefitinib + anlotinib in gefitinib‐resistant lung adenocarcinoma models in vitro and in vivo. We then investigated the treatment effect of EGFR–TKI + anlotinib therapy in 24 advanced EGFR‐mutant NSCLC patients after EGFR‐TKI acquired resistance between January 2018 and August 2020. Results: Anlotinib reversed gefitinib resistance in gefitinib‐resistant lung adenocarcinoma models by enhancing the antiproliferative and proapoptotic effects of gefitinib. The gefitinib + anlotinib treatment exerted a synergistic antitumor effect by downregulating the activation of VEGFR2 and downstream effectors, Akt and ERK. The EGFR–TKI + anlotinib therapy exhibited an objective response rate of 20.8% and a disease control rate of 95.8%. Median progression‐free survival (PFS) was 11.53 ± 2.41 months, but median overall survival was not reached. The median PFS was longer in patients experiencing gradual progression (13.30 ± 1.69 months) than in patients with dramatic progression (6.80 ± 1.75 months, p = 0.017). One grade 3 adverse event was noted (diarrhea, n = 2, 8.3%), and grade 4 or 5 adverse events were absent. Conclusions: EGFR–TKI combined with anlotinib demonstrated powerful antitumor activity in vitro and in vivo. Concurrent use of anlotinib overcomes acquired resistance to EGFR‐TKI in advanced EGFR‐mutant NSCLC patients. [ABSTRACT FROM AUTHOR]

Objective: Kanglaite(KLT), a type of Chinese medicine preparation, is considered as an adjuvant therapeutic option for malignant cancer treatment. This study aimed to systematically investigate the efficacy and safety of the combination of KLT and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) for the treatment of stage III/IV non-small cell lung cancer. Methods: Randomized controlled trials (RCTs) that compared KLT plus EGFR-TKI with EGFR-TKI alone for the treatment of stage III/IV non-small cell lung cancer were reviewed. Literature searches (up to July 10, 2021) were performed on PubMed, Web of Science, Cochrane Library, Embase, ClinicalTrials.gov, China National Knowledge Infrastructure (CNKI), Wanfang Database, and the Chinese Scientific Journal Database. Two researchers independently assessed the risk of bias with the tool of Cochrane Collaboration. RevMan 5.3.0 was used in the analysis of the included trial data. Results: 12 RCTs recruiting 1,046 patients with stage III/IV NSCLC were included. Results showed that compared with EGFR-TKI alone, KLT plus EGFR-TKI significantly increased the disease control rate (DCR) (odds ratio [OR]=3.26; 95% confidence interval [CI]:2.22–4.77; p < 0.00001), the objective response rate (ORR) (OR=2.59; 95% CI:1.87–3.58; p < 0.00001) and Karnofsky performance status (KPS) (OR = 2.76; 95% CI:1.73–4.39; p < 0.00001). Furthermore, patient immunity was enhanced with KLT plus EGFR-TKI. The combined treatment increased the percentage of CD4 + T cells (weighted mean difference [WMD]=5.36; 95% CI:3.60–7.13; p < 0.00001),the CD4+/CD8 + ratio (WMD = 0.18; 95% CI: 0.08–0.27; p = 0.004), and percentage of NK cells (WMD=4.84; 95% CI: 3.66–6.02; p < 0.00001).With regard to drug toxicity, the occurrence rate of nausea and vomiting was significantly reduced by KLT plus EGFR-TKI (OR=0.37; 95% CI: 0.16–0.86; p = 0.02). Conclusion: KLT plus EGFR-TKI was effective in treating stage III/IV non-small cell lung cancer. Thus, its application in these patients is worth promoting. Additional double-blind, well-designed and multicenter RCTs are required to confirm the efficacy and safety of this treatment. [ABSTRACT FROM AUTHOR]

Background and Objectives: Epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) are effective first-line chemotherapeutic agents for patients with advanced non-smallcell lung cancer (NSCLC) harboring drug-sensitive EGFR mutations. However, the effectiveness of EGFR-TKI rechallenge after first-line EGFR-TKI treatment is not sufficient in elderly patients (over 75 years of age) harboring drug-sensitive EGFR mutations. Therefore, we investigated the effectiveness and safety of EGFR-TKI rechallenge after first-line EGFR-TKI treatment in elderly patients with advanced NSCLC harboring drug-sensitive EGFR mutations. Materials and Methods: Between April 2008 and December 2015, we analyzed 78 elderly patients with advanced NSCLC harboring drug-sensitive EGFR mutations with first-line EGFR-TKI treatment at four Japanese institutions. We retrospectively evaluated the clinical effectiveness and safety profiles of EGFR-TKI rechallenge after first-line EGFR-TKI treatment in elderly patients with advanced NSCLC harboring drug-sensitive EGFR mutations (exon 19 deletion/exon 21 L858R mutation). Results: Twenty-two patients in the cohort were rechallenged with EGFR-TKI. The median age was 79.5 years (range 75–87 years). Despite the fact that it was a retrospective analysis, even with EGFR-TKI rechallenge treatment the response rate was 23%, progression-free survival was 5.3 months, and overall survival was 14.4 months. Common adverse events included rash acneiform, paronychia, diarrhea, and anorexia. There were no treatment-related deaths. Due to the occurrence of adverse events of grade 2 or more, dose reduction was performed in 15 (68.2%) of 22 cases. Conclusions: EGFR-TKI rechallenge treatment after first-line EGFR-TKI treatment in elderly patients with advanced NSCLC harboring drug-sensitive EGFR mutations was one of the limited, safe and effective treatment options for elderly EGFR-positive lung cancer patients. [ABSTRACT FROM AUTHOR]

Background: Tyrosine kinase inhibitors that act against epidermal growth factor receptor (EGFR) show strong efficacy against non-small cell lung cancer (NSCLC) involving mutated EGFRs. However, most such patients eventually develop resistance to EGFR-TKIs. Numerous researches have reported that messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs) may be involved in EGFR-TKI resistance, but the comprehensive expression profile and competitive endogenous RNA (ceRNA) regulatory network between mRNAs and ncRNAs in EGFR-TKI resistance of NSCLC are incompletely known. We aimed to define a ceRNA regulatory network linking mRNAs and non-coding RNAs that may mediate this resistance.Methods: Using datasets GSE83666, GSE75309 and GSE103352 from the Gene Expression Omnibus, we identified long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and mRNAs differentially expressed between NSCLC cells that were sensitive or resistant to EGFR-TKIs. The potential biological functions of the corresponding differentially expressed genes were analyzed based KEGG pathways. We combined interactions among lncRNAs, miRNAs and mRNAs in the RNAInter database with KEGG pathways to generate transcriptional regulatory ceRNA networks associated with NSCLC resistance to EGFR-TKIs. Kaplan-Meier analysis was used to assess the ability of core ceRNA regulatory sub-networks to predict the progression-free interval and overall survival of NSCLC. The expression of two core ceRNA regulatory sub-networks in NSCLC was validated by quantitative real-time PCR.Results: We identified 8,989 lncRNAs, 1,083 miRNAs and 3,191 mRNAs that were differentially expressed between patients who were sensitive or resistant to the inhibitors. These DEGs were linked to 968 biological processes and 31 KEGG pathways. Pearson analysis of correlations among the DEGs of lncRNAs, miRNAs and mRNAs identified 12 core ceRNA regulatory sub-networks associated with resistance to EGFR-TKIs. The two lncRNAs ABTB1 and NPTN with the hsa-miR-150–5p and mRNA SERPINE1 were significantly associated with resistance to EGFR-TKIs and survival in NSCLC. These lncRNAs and the miRNA were found to be down-regulated, and the mRNA up-regulated, in a resistant NSCLC cell line relative to the corresponding sensitive cells.Conclusion: In this study, we provide new insights into the pathogenesis of NSCLC and the emergence of resistance to EGFR-TKIs, based on a lncRNA-miRNA-mRNA network.

Objective: Kanglaite(KLT), a type of Chinese medicine preparation, is considered as an adjuvant therapeutic option for malignant cancer treatment. This study aimed to systematically investigate the efficacy and safety of the combination of KLT and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) for the treatment of stage III/IV non-small cell lung cancer.Methods: Randomized controlled trials (RCTs) that compared KLT plus EGFR-TKI with EGFR-TKI alone for the treatment of stage III/IV non-small cell lung cancer were reviewed. Literature searches (up to July 10, 2021) were performed on PubMed, Web of Science, Cochrane Library, Embase, ClinicalTrials.gov, China National Knowledge Infrastructure (CNKI), Wanfang Database, and the Chinese Scientific Journal Database. Two researchers independently assessed the risk of bias with the tool of Cochrane Collaboration. RevMan 5.3.0 was used in the analysis of the included trial data.Results: 12 RCTs recruiting 1,046 patients with stage III/IV NSCLC were included. Results showed that compared with EGFR-TKI alone, KLT plus EGFR-TKI significantly increased the disease control rate (DCR) (odds ratio [OR]=3.26; 95% confidence interval [CI]:2.22–4.77; p < 0.00001), the objective response rate (ORR) (OR=2.59; 95% CI:1.87–3.58; p < 0.00001) and Karnofsky performance status (KPS) (OR = 2.76; 95% CI:1.73–4.39; p < 0.00001). Furthermore, patient immunity was enhanced with KLT plus EGFR-TKI. The combined treatment increased the percentage of CD4 + T cells (weighted mean difference [WMD]=5.36; 95% CI:3.60–7.13; p < 0.00001),the CD4+/CD8 + ratio (WMD = 0.18; 95% CI: 0.08–0.27; p = 0.004), and percentage of NK cells (WMD=4.84; 95% CI: 3.66–6.02; p < 0.00001).With regard to drug toxicity, the occurrence rate of nausea and vomiting was significantly reduced by KLT plus EGFR-TKI (OR=0.37; 95% CI: 0.16–0.86; p = 0.02).Conclusion: KLT plus EGFR-TKI was effective in treating stage III/IV non-small cell lung cancer. Thus, its application in these patients is worth promoting. Additional double-blind, well-designed and multicenter RCTs are required to confirm the efficacy and safety of this treatment.

Introduction: It has been well established that EGFR Thr790Met is one of the major resistance mechanisms to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs). Nevertheless, whether EGFR Thr790Leu (T790L), which shares the mutation site of Thr790 with EGFR Thr790Met, mediates resistance to EGFR TKIs remains elusive. The treatment options for patients harboring this rare mutation have not been reported. Methods: Capture-based targeted ultradeep sequencing was performed on tumor and plasma samples collected at various treatment milestones from three patients with advanced lung adenocarcinoma undergoing targeted therapy. Results: Needle biopsy of lymph node metastasis from patient 1 revealed EGFR T790L at disease progression on first-line treatment of gefitinib. Patient 2 had EGFR T790L identified from needle biopsy of lung tissue at disease progression on icotinib treatment. This patient was subsequently treated with osimertinib and achieved stable disease with a progression-free survival of 9 months. For patient 3, at disease recurrence after surgery, resected lung tumor tissue was retrieved for molecular profiling and revealed EGFR exon 19 deletion and EGFR T790L. The patient subsequently received osimertinib treatment and continued to benefit for 16 months and counting. She has maintained stable disease at the time of submission of this manuscript. Conclusions: We revealed for the first time that EGFR T790L may serve as a potential resistance mechanism to first-generation EGFR TKIs. We also report the first clinical evidence of efficacy generated by osimertinib in patients with lung adenocarcinoma harboring primary or acquired EGFR T790L, shedding light on treatment options for this subset of patients.

First-generation EGFR-TKIs (gefitinib/erlotinib) and second-generation EGFR-TKI (afatinib) have become the current first-line treatments for EGFR-mutated non-small cell lung cancer (NSCLC), however, the effects of using second-generation EGFR-TKIs compared to those of using first-generation EGFR-TKIs as a first-line treatment for NSCLC patients with EGFR mutations remain unknown. We conducted this meta-analysis based on 4 retrospective and 2 randomized controlled studies published between 2016 and 2018. We surveyed the effectiveness of afatinib/dacomitinib and gefitinib/erlotinib as first-line treatments for stage III-IV EGFR-mutated NSCLC patients. The combined hazard ratio (HR) for the progression free survival (PFS) of second-generation EGFR-TKI group versus that first-generation drug group was 0.64 [95% confidence interval (95% CI) 0.55-0.74; P<0.001], demonstrating a superior PFS in the second-generation group. This outcome coincided with the subgroup analyses comparing the PFS of patients with EGFR exon 19 deletion (HR = 0.68 [95% CI 0.55-0.83; P = 0.0002]) or L858R mutation (HR = 0.64 [95% CI 0.51-0.81; p=0.0002]). Meanwhile, second-generation drugs could to significantly improve the time to progression (TTFs) compared to first-generation drugs (HR = 0.81 [95% CI 0.67-0.89; P = 0.03]). Afatinib and dacomitinib may be the superior first-line treatment for advanced NSCLC patients with EGFR mutations. [ABSTRACT FROM AUTHOR]

A 60-year-old woman was diagnosed with cT4N3M1c stage IVB lung adenocarcinoma with epidermal growth factor receptor mutation of exon19 deletion. After one month of treatment with osimertinib, a cough and diffuse ground glass opacities were observed in the bilateral lung field. Based on the clinical course and the exclusion of other etiologies, osimertinib-induced pneumonitis was diagnosed. The shadows resolved after osimertinib was discontinued. However, brain metastasis and leptomeningeal metastasis developed 20 months later; therefore, osimertinib was re-administered without concomitant corticosteroids. The pulmonary lesion and leptomeningeal metastasis were successfully treated without recurrence of drug-induced pneumonitis for eight months. [ABSTRACT FROM AUTHOR]

Abstract Background Non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations often develop brain metastases. Treatment with EGFR-tyrosine kinase inhibitors (TKIs) has shown the effectiveness; however, knowledge of the clinical factors associated with outcomes in NSCLC patients with EGFR mutations remains limited. Methods Treatment-naive patients diagnosed with advanced non-squamous NSCLC with brain metastases harboring EGFR mutations and treated with an EGFR-TKI as first-line therapy were enrolled with analysis of their medical records. Results A total of 134 advanced NSCLC patients with brain metastases harboring EGFR mutations received an EGFR-TKI (gefitinib: 62, erlotinib: 49, and afatinib: 23) as the first-line therapy. Sixty-nine had exon 19 deletions (51.5%), and 56 (41.8%) had L858R mutations. There was no statistically significant difference in progression-free survival (PFS) and overall survival (OS) among the EGFR-TKIs. Significantly shorter OS was noted in patients with multiple brain metastases (hazard ratio [HR]: 2.43, p = 0.007), uncommon EGFR mutations (HR: 3.75, p = 0.009), and liver metastases. Thirty-eight patients (29.1%) received brain radiotherapy for brain metastases before disease progression, and had a significantly longer time until intracranial progression. However, the brain radiotherapy had no statistically significant impact on PFS or OS. Conclusions Patients with uncommon mutations, multiple brain metastases, and concomitant liver metastases tended to have shorter OS. Brain radiotherapy could delay the time to intracranial disease progression but had no impact on survival. The different first-line EGFR-TKIs achieved similar treatment responses in terms of PFS and OS in the EGFR-mutated NSCLC patients with brain metastases.

Zhen Wu, Yu Dai, Liang-An Chen Respiratory Department, Chinese PLA General Hospital, Beijing, People’s Republic of ChinaCorrespondence: Liang-An ChenRespiratory Department of Chinese PLA General Hospital, IMB 16th Floor, Room 16-104 28, Fuxing road, Haidian district, Beijing 100853, People’s Republic of ChinaTel +86 10 6693 6184Email chenliangan301@163.comPurpose: To investigate the association between level of serum ferritin (SF) and epidermal growth factor receptor (EGFR) mutations and to analyse the impact of SF level on survival times in advanced non-small-cell lung cancer (NSCLC) patients taking EGFR tyrosine kinase inhibitors (EGFR-TKIs).Methods: A total of 301 patients who were admitted to the Chinese PLA general hospital from August 2015 to August 2017 were enrolled. The association between tumour markers, including SF, CEA, and EGFR mutation, and their impact on the prognosis of patients taking EGFR-TKIs was investigated.Results: In all patients, the percentage of patients with EGFR mutations was 52.5% (158/301). EGFR mutations were more likely to be detected in younger (258 μg/L (>258 μg/L for females or >658 μg/L for males) p

Background The aim of this study was to investigate the feasibility of using a combination of apatinib in the treatment of non‐small cell lung cancer. Apatinib is a tyrosine kinase inhibitor which selectivelyacts on vascular endothelial growth factor receptor 2 (VEGFR‐2) and has shown good efficacy in a variety of malignancies, but the drug resistance is fast in single drug therapy. Methods The inhibitory effect of apatinib and other drugs on lung cancer cells was determined by CCK‐8 test in vitro, and the IC50 value was determined. To establish a nude mouse xenograft model, observe the inhibitory effect of apatinib combined with other drugs on lung cancer xenografts in nude mice; immunohistochemical staining of tumor microvessel density and Ki67 expression in transplanted tumor tissues; Western blot analysis of related signaling pathways expression; immunohistochemistry was used to detect tumor microvessel density in other organs and to observe its safety. Results In this study, we found apatinib combined with pemetrexed, the first and third generation of epidermal growth factor receptor tyrosine kinase inhibitor, could synergistically inhibit the proliferation of non‐small cell lung cancer cell (NSCLC) lines, reduce the microvessel density and Ki67 protein levels of three non‐small cell lung cancer xenografts, and enhance anti‐tumor activity by synergistically inhibiting the MAPK‐ERK and PI3K‐AKT‐mTOR signaling pathway. Furthermore, there were no pathological abnormalities in the heart, brain, liver and kidney of each group. Conclusions The efficacy of apatinib combination is better than that of monotherapy, and there is no significant difference in toxicity of important organs, which suggests the feasibility of a combination of apatinib in the treatment of non‐small cell lung cancer.

Background Non‐small cell lung cancer (NSCLC) positive for activating mutations of the epidermal growth factor receptor (EGFR) gene is initially sensitive to EGFR‐tyrosine kinase inhibitors (TKIs) but eventually develops resistance to these drugs. Upregulation of the receptor tyrosine kinase AXL in tumor tissue has been detected in about one‐fifth of NSCLC patients with acquired resistance to EGFR‐TKIs. However, the clinical relevance of the levels of AXL and its ligand GAS6 in plasma remains unknown. Methods Tumor tissue and plasma specimens were collected from 25 EGFR‐mutated NSCLC patients before EGFR‐TKI treatment or after treatment failure. The levels of AXL and of GAS6 mRNA in tumor tissue were evaluated by immunohistochemistry and chromogenic in situ hybridization, respectively. The plasma concentrations of AXL and GAS6 were measured with enzyme‐linked immunosorbent assays. Results AXL expression was detected in three of 12 (25%) and nine of 19 (47%) tumor specimens obtained before and after EGFR‐TKI treatment, respectively. All tumor specimens assayed were positive for GAS6 mRNA. The median values for the plasma AXL concentration before and after EGFR TKI treatment were 1 635 and 1 460 pg/mL, respectively, and those for the plasma GAS6 concentration were 4 615 and 6 390 pg./mL, respectively. There was no significant correlation between the plasma levels of AXL or GAS6 and the corresponding expression levels in tumor tissue. Conclusion Plasma concentrations of AXL and GAS6 do not reflect tumor expression levels, and their measurement is thus not a viable alternative to direct analysis of tumor tissue in EGFR‐mutated NSCLC.

Abstract Background Approximately 30% of patients with epidermal growth factor receptor (EGFR)-activating mutations have no response to EGFR-tyrosine kinase inhibitors (TKIs) (primary resistance). However, little is known about the molecular mechanism involved in primary resistance to EGFR-TKIs in EGFR-mutant non-small cell lung cancer (NSCLC). Programmed death ligand-1 (PD-L1) plays important regulatory roles in intracellular functions and leads to acquired resistance to EGFR-TKIs in NSCLC. Here, we investigated the mechanistic role of PD-L1 in primary resistance to EGFR-TKIs in EGFR-mutant NSCLC cells. Methods The expression levels of PD-L1 and the sensitivity to gefitinib in H1975, HCC827 and PC-9 cells were determined by quantitative real-time PCR analysis (qRT-PCR) and Cell Counting Kit-8 (CCK-8) assays, respectively. Molecular manipulations (silencing or overexpression) were performed to assess the effect of PD-L1 on sensitivity to gefitinib, and a mouse xenograft model was used for in vivo confirmation. Western blotting and qRT-PCR were used to analyse the expression of epithelial-mesenchymal transition (EMT) markers. The effect of PD-L1 on migratory and invasive abilities was evaluated using the Transwell assay and mice tail intravenous injection. Results Higher expression of PD-L1 was related to less sensitivity to gefitinib in EGFR-mutant NSCLC cell lines. The overexpression or knockdown of PD-L1 presented diametrical sensitivity to gefitinib in vitro and in vivo. Furthermore, the overexpression of PD-L1 led to primary resistance to gefitinib through the induction of EMT, which was dependent on the upregulation of Smad3 phosphorylation. Moreover, in the mouse model, the knockdown of PD-L1 inhibited transforming growth factor (TGF)-β1-induced cell metastasis in vivo. Conclusion PD-L1 contributes to primary resistance to EGFR-TKI in EGFR-mutant NSCLC cells, which may be mediated through the induction of EMT via the activation of the TGF-β/Smad canonical signalling pathway.

Background The aim of our study was to retrospectively assess the incidence of interstitial lung disease (ILD) related to EGFR‐tyrosine kinase inhibitor (TKI) treatment immediately before and/or after the administration of a PD‐1 antibody. Methods We analyzed the data of 26 patients who underwent treatment with EGFR‐TKIs immediately before and/or after the administration of an anti‐PD‐1 antibody. Results Four out of the 26 patients developed ILD during EGFR‐TKI treatment: three patients during the administration of osimertinib immediately after, and one during afatinib immediately before treatment with an anti‐PD‐1 antibody. Three of 12 patients who underwent EGFR‐TKI therapy immediately after anti‐PD‐1 antibody treatment experienced osimertinib‐induced ILD. ILD was not observed in the five patients administered an anti‐PD‐1 antibody followed by first or second‐generation EGFR‐TKIs. Conclusion ILD was observed in the treatment sequence of an anti‐PD‐1 antibody followed by osimertinib, but not with first or second‐generation EGFR‐TKIs.

ErbB receptor tyrosine kinase inhibitors (EGFR-TKI), gefitinib, erlotinib, icotinib and aftinib, which are approved as a frontline treatment for patients with non-small cell lung cancer (NSCLC) who have tumors harboring EGFR mutations in China. And osimertinib was approved in second line setting for patients with EGFRT 790M-positive NSCLC. Rash, paronychia, diarrhea, stomatitis, liver dysfunction and (interstitial lung disease, ILD) are frequently observed in patients treated with EGFR-TKI. Chinese Society of Lung Cancer, Chinese Anti-Cancer Association, organized Chinese experts to develop the Chinese expert consensus on EGFR-TKI adverse event (AE) management based on domestic diagnosis and treatment of ADR and also incorporating international updated theory and recommendations.

Tyrosine kinase inhibitor (TKI) have been proved to be effective in the treatment of advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) sensitive mutation, which is superior to chemotherapy. However, there are still some patients with sensitive mutations have primary drug resistance. It may be related to the coexistence of susceptible and resistant mutations of EGFR gene, downstream mutations of EGFR pathway, MET amplification and BIM deletion polymorphism. We present 2 cases of primary drug resistance and analyze the reasons.

Drug resistance is a common barrier to continued effective treatment in cancer. In non-small-cell lung cancer (NSCLC), tyrosine kinase inhibitors that target the epidermal growth factor receptor (EGFR-TKIs) exhibit good efficacy in cancer treatment until acquired resistance occurs. It has been observed that drug resistance is accompanied by numerous molecular-level changes, including significant shifts in cellular metabolism. The purpose of this study was to critically and systematically review the published literature with respect to how metabolism differs in drug-resistant compared to drug-sensitive NSCLC. Understanding the differences between resistant and sensitive cells is vital and has the potential to allow interventions that enable the re-sensitisation of resistant cells to treatment, and consequently reinitiate the therapeutic effect of EGFR-TKIs. The main literature search was performed using relevant keywords in PubMed and Ovid (Medline) and reviewed using the Covidence platform. Of the 1331 potentially relevant literature records retrieved, 27 studies were subsequently selected for comprehensive analysis. Collectively, the literature revealed that NSCLC cell lines resistant to EGFR-TKI treatment possess characteristic metabolic and lipidomic phenotypic signatures that differentiate them from sensitive lines. Further exploration of these reported differences suggests that drug-resistant cell lines are differentially reliant on cellular energy sources and that modulation of relative energy production pathways may lead to the reversal of drug resistance.

Non-small cell lung cancer (NSCLC) is the most common lung cancer subtype. Although chemotherapy and targeted therapy are used for the treatment of patients with NSCLC, the survival rate remains very low. Recent findings suggested that aurora kinase A (AKA), a cell cycle regulator, is a potential target for NSCLC therapy. Previously, we reported that a chemical entity of quinazolin-4(3H)-one represents a new template for AKA inhibitors, with antiproliferative activity against cancer cells. A quinazolin-4(3H)-one derivative was further designed and synthesized in order to improve the pharmacokinetic properties and antiproliferation activity against NSCLC cell lines. The derivative, BIQO-19 (Ethyl 6-(4-oxo-3-(pyrimidin-2-ylmethyl)-3,4-dihydroquinazolin-6-yl)imidazo [1,2-a]pyridine-2-carboxylate), exhibited improved solubility and antiproliferative activity in NSCLC cells, including epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI)-resistant NSCLC cells. BIQO-19 effectively inhibited the growth of the EGFR-TKI-resistant H1975 NSCLC cells, with the suppression of activated AKA (p-AKA) expression in these cells. The inhibition of AKA by BIQO-19 significantly induced G2/M phase arrest and subsequently evoked apoptosis in H1975 cells. In addition, the combination of gefitinib and BIQO-19 exhibited synergistic antiproliferative activity in NSCLC cells. These findings suggest the potential of BIQO-19 as a novel therapeutic agent for restoring the sensitivity of gefitinib in EGFR-TKI-resistant NSCLC cells.