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Anaplastic lymphoma kinase (ALK) fusions account for 5-7% of non-small cell lung cancer (NSCLC) patients, the therapeutic approaches for which have significantly evolved in the last few years. However, the response to target therapies remains heterogeneous, partially due to the many different ALK fusion variants reported to date. Rare fusion variants have also been discovered, but their role in influencing responses to ALK inhibitors (ALKis) remains poorly elucidated. Laboratory investigation at both the tissue and protein levels, and a molecular profile by next-generation sequencing (NGS) were performed on a lung biopsy sample from one patient with poorly differentiated adenocarcinoma. An in silico prediction model using ColabFold software v1.5.5 was used to model and predict the entire structure of the chimeric aberrant ALK protein. Here, we report a case of a former smoker, a 60-year-old man, diagnosed with NSCLC and undergoing ALK translocation. He received first-, second- and third-generation ALK protein inhibitors (ALKis), showing a clinical benefit for about 4 years. IHC analysis and the molecular examination of the tissue biopsy indicated a positive staining for ALK and a novel ALK gene fusion variant, involving the sperm antigen with calponin homology and coiled-coil domain 1-like (SPECC1L) gene with an unreported breakpoint in exon 7. The novel SPECCL1::ALK fusion was identified using Anchored Multiplex PCR (AMP)-NGS technology and was predicted to retain the Pkinase_Tyr domain at the carboxy-terminal region of the resulting chimeric protein. To the best of our knowledge, this is the first case of an ALK-positive NSCLC patient carrying the SPECC1L exon 7 fusion breakpoint and one of the few reports about clinical outcomes related to SPECC1L::ALK fusion. The in silico hypothesized biological role of this newly identified fusion variant corroborates the observed clinical response to multiple ALKis. The molecular findings also reinforce the utility of AMP-based NGS technology as a valuable tool for the identification of rare chromosomal events that may be related to the variability of patient outcomes to different ALKis treatments.

Background: Alectinib significantly improves survival of non-small cell lung cancer (NSCLC) patients with anaplastic lymphoma kinase ( ALK )-rearrangement. In this study, we analyzed the effects of different ALK rearrangements and co-mutations on the efficacy of alectinib., Methods: Using the electronic medical record system, we reviewed in terms of clinical and pathological features patients with advanced (IIIB/IV stage) ALK -rearranged NSCLC at Shanghai Chest Hospital between January 2018 and December 2021 who were treated with alectinib in first or second line and were assessed for objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS)., Results: A total of 66 patients were enrolled in the study, and 17 types of ALK rearrangements were detected, of which five types of ALK rearrangements responded well to alectinib. We classified ALK -rearrangements into four main types, namely echinoderm microtubule-associated protein-like 4 ( EML4 )- ALK (E6:A20), EML4-ALK (E13:A20), EML4-ALK (E20:A20), and others. There was no significant difference in ORR and DCR of these types (ORR: 31.3% vs. 13.0% vs. 18.2% vs. 17.6%, P=0.575; DCR: 93.8% vs. 95.6% vs. 100.0% vs. 88.2%, P=0.627). The 3-year PFS rates were 25.0% (4/16) vs. 13.0% (3/23) vs. 27.3% (3/11) vs. 18.8% (3/16) for EML4-ALK (E6:A20), EML4-ALK (E13:A20), EML4-ALK (E20:A20), and others, respectively (P=0.725). The results of co-mutation analysis showed that the median PFS (mPFS) for patients with tumors harboring TP53 mutations was 30.4 months, significantly shorter than that of patients with tumors without co-mutations and whose mPFS was not mature (P=0.026). TSC1 co-mutation was also identified as a detrimental factor in outcome, with a DCR of 60% vs. 100% (P=0.031), mPFS of 30.4 months vs. not applicable (P=0.160) in patients with vs. those without this co-mutation, respectively. The efficacy of alectinib in patients with brain metastases is comparable to that in patients without distant organ metastases. There were two cases with specific fusion types that also responded to alectinib; namely, double ALK -rearrangements: EML4-ALK (E13:A20) and MSH2-ALK (M7:A20), and with a rare fusion partner, SPECC1L-ALK (S8:A20). Their PFS were 8.7 and 38.0 months, respectively., Conclusions: In this study, the efficacy of alectinib in different types of ALK -rearrangements varied slightly. TP53 and TSC1 co-mutations were identified as detrimental factors affecting efficacy. This study provides references for the response to alectinib in patients with different types of ALK rearrangements and co-mutation., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-658/coif). Y.Z. and X.Z. are from 3D Medicines Inc., Shanghai, China. A.R. has received advisory board honoraria from AstraZeneca, MSD, Novartis, Pfizer, BMS, and Amgen; writing engagement honoraria from AstraZeneca, MSD, Roche and Novartis; speaker bureau from AstraZeneca and BMS. A.R. reports research funding from EMQN, GECP; consulting fees from AstraZeneca; payment or honoraria for lectures, presentations, speaker bureaus from Thermofisher Scientific, Illumina, Health in code; and travel expenses from Thermofisher Scientific, Bristol Myers Squibb Foundation, Takeda. She also serves as advisory board member in Takeda. E.M.U. reports honoraria for lectures from Amgen, AstraZeneca, Janssen, Novartis; support from AstraZeneca for participation at IASLC WCLC 2023, Singapore, and advisory board member in Pfizer, Roche, Takeda. The other authors have no conflicts of interest to declare., (2023 Translational Lung Cancer Research. All rights reserved.)

Purpose: The response to immune checkpoint inhibitors (ICI) often differs between genders in non-small cell lung cancer (NSCLC), but metanalyses results are controversial, and no clear mechanisms are defined. We aim at clarifying the molecular circuitries explaining the differential gender-related response to anti-PD-1/anti-PD-L1 agents in NSCLC., Experimental Design: We prospectively analyzed a cohort of patients with NSCLC treated with ICI as a first-line approach, and we identified the molecular mechanisms determining the differential efficacy of ICI in 29 NSCLC cell lines of both genders, recapitulating patients' phenotype. We validated new immunotherapy strategies in mice bearing NSCLC patient-derived xenografts and human reconstituted immune system ("immune-PDXs")., Results: In patients, we found that estrogen receptor α (ERα) was a predictive factor of response to pembrolizumab, stronger than gender and PD-L1 levels, and was directly correlated with PD-L1 expression, particularly in female patients. ERα transcriptionally upregulated CD274/PD-L1 gene, more in females than in males. This axis was activated by 17-β-estradiol, autocrinely produced by intratumor aromatase, and by the EGFR-downstream effectors Akt and ERK1/2 that activated ERα. The efficacy of pembrolizumab in immune-PDXs was significantly improved by the aromatase inhibitor letrozole, which reduced PD-L1 and increased the percentage of antitumor CD8+T-lymphocytes, NK cells, and Vγ9Vδ2 T-lymphocytes, producing durable control and even tumor regression after continuous administration, with maximal benefit in 17-β-estradiol/ERα highfemale immune-xenografts., Conclusions: Our work unveils that 17-β-estradiol/ERα status predicts the response to pembrolizumab in patients with NSCLC. Second, we propose aromatase inhibitors as new gender-tailored immune-adjuvants in NSCLC. See related commentary by Valencia et al., p. 3832., (©2023 American Association for Cancer Research.)

Background: The Italian Register of Actionable Mutations (RATIONAL) is a multicentric, observational study collecting next-generation sequencing (NGS)-based tumour profiling data of patients with advanced solid tumours., Methods: The study enrols patients who had available an NGS-based tumour profiling (Pathway-A) or undergo comprehensive genomic profiling (CGP) with FoundationOne CDx assays within the trial (Pathway-B). The primary endpoint was the rate of actionable mutations identified., Results: Sequencing data were available for 738 patients in Pathway-A (218) and -B (520). In Pathway-A, 154/218 (70.6%) tests were performed using NGS panels ≤52 genes, and genomic alterations (GAs) were found in 164/218 (75.2%) patients. In Pathway-B, CGP revealed GAs in 512/520 (98.5%) patients. Levels I/II/III actionable GAs according to the European Society of Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT) were identified in 254/554 (45.8%) patients with non-small-cell lung cancer, cholangiocarcinoma, colorectal, gastric, pancreatic and breast cancer. The rate of patients with level I GAs was similar in Pathways A and B (69 versus 102). CGP in Pathway-B revealed a higher number of patients with level II/III GAs (99 versus 20) and potentially germline pathogenic/likely pathogenic variants (58 versus 15) as compared with standard testing in Pathway-A. In patients with cancer of unknown primary, CGP detected OncoKB levels 3B/4 GAs in 31/58 (53.4%) cases. Overall, 67/573 (11.7%) of patients received targeted therapy based on genomic testing., Conclusion: The Italian Register of Actionable Mutations represents the first overview of genomic profiling in Italian current clinical practice and highlights the utility of CGP for identifying therapeutic targets in selected cancer patients., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: N. Normanno declares: speaker’s fee and/or advisory boards from MSD, Bayer, Biocartis, Illumina, Incyte, Roche, BMS, Merck, Thermofisher, AstraZeneca, Eli Lilly; financial support to research projects (institutional grants) from Merck, Thermofisher, QIAGEN, Roche, AstraZeneca, Biocartis, Illumina; non-financial interests President of the International Quality Network for Pathology (IQN Path) and Past President of the Italian Cancer Society (SIC). G. Curigliano declares: speaker’s fee/consulting fees/travel support from BMS, Roche, Pfizer, Novartis, Lilly, AstraZeneca, Daichii Sankyo, Merck, Seagen, Ellipsis, Gilead, Pfizer, Relay. V. Guarneri declares: speaker’s fee/consulting fees/travel support from EliLilly, Amgen, GSK, Gilead, AstraZeneca, Eisai, Exact Sciences, Merck Serono, MSD, Novartis, Olema Oncology, Sanofi. V. Adamo declares: speaker’s fee/consulting fees/travel support from Pfizer, MSD, Amgen, BMS, Novartis, AstraZeneca, Lilly. G. L. Frassineti declares: speaker’s fee/consulting fees/travel support from Servier, Merck, Bayer, MSD. B. Daniele declares: speaker’s fee/consulting fees/travel support from EISAI, Ipsen, AstraZeneca, ROCHE, Amgen, MSD, Sanofi. A. Morabito declares: speaker’s fee/consulting fees/travel support from Roche, MSD, AstraZeneca, Novartis, Boehringer, Lilly, Takeda, BMS, Pfizer. G. Fasola declares: speaker’s fee/consulting fees/travel support from Servier, Asytazeneca, Eubea, VyvaMed, MI&T, A&G, GSK, BMS, Merck, Ipsen. Roche, F. Tabbò declares: speaker’s fee/consulting fees/travel support from Roche, AstraZeneca. Takeda, C. Masini declares consulting fees from BMS, Astellas, Janssen, MSD, Ipsen. C. Pinto declares personal fees from Amgen, Astellas, AstraZeneca, Bayer, Bristol Meyer Squibb, Celgene, Clovis Oncology, Eisai, Ipsen, Janssen, Incyte, Merck-Serono, Merck Sharp and Dohme, Novartis, Roche, Sandoz, Sanofi, and Servier, A. De Luca declares no conflict of interest. R. Esposito Abate declares no conflict of interest. M. Milella declares grants or contracts from Roche and Novartis, payment for consulting fees from Viatris, AstraZeneca, MSD, and Merck; payment for participation on a Data Safety Monitoring Board or Advisory Board from Novartis. P. Marchetti PM declares consultant/advisory role for BMS, Roche, Genentech, MSD, Novartis, Amgen, Merck Serono, Pierre Fabre, and Incyte. G. Pruneri declares honoraria from Novartis, Roche, Lilly and Exact Science. R. Berardi declares consultant/advisory board activities for AstraZeneca, Boehringer Ingelheim, Novartis, MSD, Otsuka, Eli-Lilly, Roche. F. Feroce declares no conflict of interest. E. Maiello declares no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) show potent efficacy in several ALK-driven tumors, but the development of resistance limits their long-term clinical impact. Although resistance mechanisms have been studied extensively in ALK-driven non-small cell lung cancer, they are poorly understood in ALK-driven anaplastic large cell lymphoma (ALCL). Here, we identify a survival pathway supported by the tumor microenvironment that activates phosphatidylinositol 3-kinase γ (PI3K-γ) signaling through the C-C motif chemokine receptor 7 (CCR7). We found increased PI3K signaling in patients and ALCL cell lines resistant to ALK TKIs. PI3Kγ expression was predictive of a lack of response to ALK TKI in patients with ALCL. Expression of CCR7, PI3Kγ, and PI3Kδ were up-regulated during ALK or STAT3 inhibition or degradation and a constitutively active PI3Kγ isoform cooperated with oncogenic ALK to accelerate lymphomagenesis in mice. In a three-dimensional microfluidic chip, endothelial cells that produce the CCR7 ligands CCL19/CCL21 protected ALCL cells from apoptosis induced by crizotinib. The PI3Kγ/δ inhibitor duvelisib potentiated crizotinib activity against ALCL lines and patient-derived xenografts. Furthermore, genetic deletion of CCR7 blocked the central nervous system dissemination and perivascular growth of ALCL in mice treated with crizotinib. Thus, blockade of PI3Kγ or CCR7 signaling together with ALK TKI treatment reduces primary resistance and the survival of persister lymphoma cells in ALCL.

Background: MET-driven acquired resistance is emerging with unanticipated frequency in patients relapsing upon molecular therapy treatments. However, the determination of MET amplification remains challenging using both standard and next-generation sequencing-based methodologies. Liquid biopsy is an effective, non-invasive approach to define cancer genomic profiles, track tumor evolution over time, monitor treatment response and detect molecular resistance in advance. Circular RNAs (circRNAs), a family of RNA molecules that originate from a process of back-splicing, are attracting growing interest as potential novel biomarkers for their stability in body fluids., Methods: We identified a circRNA encoded by the MET gene (circMET) and exploited blood-derived cell-free RNA (cfRNA) and matched tumor tissues to identify, stratify and monitor advanced cancer patients molecularly characterized by high MET activity, generally associated with genomic amplification., Results: Using publicly available bioinformatic tools, we discovered that the MET locus transcribes several circRNA molecules, but only one candidate, circMET, was particularly abundant. Deeper molecular analysis revealed that circMET levels positively correlated with MET expression and activity, especially in MET-amplified cells. We developed a circMET-detection strategy and, in parallel, we performed standard FISH and IHC analyses in the same specimens to assess whether circMET quantification could identify patients displaying high MET activity. Longitudinal monitoring of circMET levels in the plasma of selected patients revealed the early emergence of MET amplification as a mechanism of acquired resistance to molecular therapies., Conclusions: We found that measurement of circMET levels allows identification and tracking of patients characterized by high MET activity. Circulating circMET (ccMET) detection and analysis could be a simple, cost-effective, non-invasive approach to better implement patient stratification based on MET expression, as well as to dynamically monitor over time both therapy response and clonal evolution during treatment., (© 2023. The Author(s).)

The identification of actionable targets in oncogene-addicted non-small cell lung cancer (NSCLC) has fueled biomarker-directed strategies, especially in advanced stage disease. Despite the undeniable success of molecular targeted therapies, duration of clinical response is relatively short-lived. While extraordinary efforts have defined the complexity of tumor architecture and clonal evolution at the genetic level, not equal interest has been given to the dynamic mechanisms of phenotypic adaptation engaged by cancer during treatment. At the clinical level, molecular targeted therapy of EGFR-mutant and ALK-rearranged tumors often results in epithelial-to-mesenchymal transition (EMT) and histological transformation of the original adenocarcinoma without the acquisition of additional genetic lesions, thus limiting subsequent therapeutic options and patient outcome. Here we provide an overview of the current understanding of the genetic and non-genetic molecular circuits governing this phenomenon, presenting current strategies and potentially innovative therapeutic approaches to interfere with lung cancer cell plasticity., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Lung cancer (LC) tissue for immunological characterization is often scarce. We explored and compared T cell characteristics between broncho-alveolar lavage from tumor affected (t-BAL) and contralateral lung (cl-BAL), with matched peripheral blood (PB)., Methods: BAL and PB were collected during bronchoscopy for diagnostic and/or therapeutic purposes in patients with monolateral primary lesion., Results: Of 33 patients undergoing BAL and PB sampling, 21 had histologically-confirmed LC. Most cases were locally-advanced or metastatic non-small cell LC. T cell characteristics were not significantly different in t-BAL vs. cl-BAL. Compared to PB, CD8 T cells in BAL presented features of immune activation and exhaustion (high PD-1, low IFN-g production). Accordingly, regulatory CD4 T cells were also higher in BAL vs. PB. When dichotomizing T cell density in t-BAL in high and low, we found that PD-L1 expression in LC was associated with T cell density in t-BAL. T-BAL with high T cell density had higher %IFN-g+CD8 T cells and lower %T-regs., Conclusion: In BAL from advanced LC patients, T cells present features of exhaustion. T cells in t-BAL could be the best surrogate of tumor-infiltrating T cell, and future studies should evaluate T cell phenotype and density as potential biomarkers for cancer immunotherapy outcome.

Introduction: Anaplastic lymphoma kinase (ALK) fusions identify a limited subset of non-small cell lung cancer (NSCLC) patients, whose therapeutic approach have been radically changed in recent years. However, diagnostic procedures and clinical-radiological responses to specific targeted therapies remain heterogeneous and intrinsically resistant or poor responder patients exist., Methods: A total of 290 patients with advanced NSCLC defined as ALK+ by immunohistochemistry (IHC) and/or fluorescent in situ hybridisation (FISH) test and treated with single or sequential multiple ALK inhibitors (ALKi) from 2011 to 2017 have been retrospectively retrieved from a multicentre Italian cancer network database. In 55 patients with enough leftover tumour tissue, specimens were analysed with both targeted and customised next generation sequencing panels. Identified fusion variants have been correlated with clinical outcomes., Results: Of the 55 patients, 24 received crizotinib as first-line therapy, 1 received ceritinib, while 30 received chemotherapy. Most of the patients (64%) received ALKi in sequence. An ALK fusion variant was identified in 73% of the cases, being V3 variant (E6A20) the most frequent, followed by V1 (E13A20) and more rare ones (e.g. E6A19). In three specimens, four new EML4-ALK fusion breakpoints have been reported. Neither fusion variants nor brain metastases were significantly associated with overall survival (OS), while it was predictably longer in patients receiving a sequence of ALKi. The presence of V1 variant was associated with progression-free survival (PFS) improvement when crizotinib was used (p = 0.0073), while it did not affect cumulative PFS to multiple ALKi., Conclusion: Outcomes to sequential ALKi administration were not influenced by fusion variants. Nevertheless, in V1+ patients a prolonged clinical benefit was observed. Fusion variant identification by NGS technology may add relevant information about rare chromosomal events that could be potentially correlated to worse outcomes., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-527/coif). CZ serves as an Editor-in-Chief of Translational Lung Cancer Research from August 2014 to July 2022. SHL serves as an unpaid editorial board member of Translational Lung Cancer Research from September 2019 to September 2023. GM serves as an unpaid editorial board member of Translational Lung Cancer Research from February 2016 to July 2023. CG serves as an unpaid editorial board member of Translational Lung Cancer Research from September 2019 to September 2023, and received honoraria as speaker bureau or advisory board member or consulting fees form Menarini, Roche, Eli Lilly, Boehringer, Amgen, Pfizer, Novartis, MSD, BMS, Astra Zeneca, Takeda, Novartis, GSK, Karyopharm. Qing Z received lecture and presentations fees from AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche, and Sanofi. AB received consulting fees as an Advisory Board with Astra Zeneca, BD, Ethicon, Medtronic, Roche, and is the president of European Society of Thoracic Surgeons. TJ received consulting fees from Roche, Merck, MSD, Puma, AstraZeneca, BMS, Amgen, Gilead, Specialised Therapeutics. DHO reports research funding (to institution) from Genentech, BMS, Merck, Pfizer, Palobiofarma, and Onc. AI. MR received honoraria for lectures and expert meetings from Astrazeneca, and also received honoraria for lectures and expert meetings as well as travel expenses from Abex. KS received a research grant from Boehringer-Ingelheim, through Kindai University Faculty of Medicine, has received consulting fees from AstraZeneca, and has received honoraria from Chugai, Taiho, and AstraZeneca. FT received speaker bureau from AstraZeneca. The other authors have no conflicts of interest to declare.

The treatment landscape of advanced non-small cell lung cancer (NSCLC) patients has dramatically changed over the past 10 years, particularly thanks to the advent and development of several tyrosine kinase inhibitors (TKI) targeting oncogenic drivers. Among them, patients bearing anaplastic lymphoma kinase (ALK) translocations, which are causative of 3-5% of all advanced NSCLC, have seen dramatically improved their clinical outcomes moving life expectancy at 5 years from less than 5% to 50%. In fact, multiple ALK inhibitors (ALKi) entered in the therapeutic algorithm of ALK+ patients, multiplying their treatment opportunities. Remarkably, in the near future we could take advantage of up to different 6 molecules for the first-line approach (crizotinib, ceritinib, alectinib, brigatinib, plus ensartinib and lorlatinib). Among available ALKi, brigatinib, a second-generation (2G) inhibitor, showed notable activity in this setting, also against central nervous system (CNS) disease, and a good safety profile, supporting its approval as upfront treatment based on the ALTA-1L trial results. With a peculiar profile of enzymatic targets, brigatinib represents a valuable opportunity in the ALK targeting journey, albeit having to balance its safety profile. The abundance of therapeutic options for these patients poses nontrivial questions; in absence of direct comparisons of efficacy is not easy to define the best approach and, more compelling, the correct administration sequence in order to give the best therapeutic chances to ALK+ lung cancer patients. In such wide variety of options, we reviewed the preclinical and clinical efficacy data of brigatinib, its pharmacological and safety profile, like also actual and potential future applications in the ALK+ NSCLC scenario. Through a spurious exercise of an indirect comparison with other available 2G ALKi, we tent to summarize the required knowledge to properly choose the best drug at the right time. Furthermore, we reviewed available data on molecular resistance mechanisms and putative therapeutic applications in other contexts, such as ROS1+ NSCLC patients or EGFR+ ones progressing to osimertinib.

c-Met inhibitors are a class of drugs that include nonselective and selective molecules. These drugs can differ in terms of pharmacodynamic and pharmacokinetic properties that may be clinically relevant. c-Met inhibitors with high potency and selectivity may allow achieving optimal c-Met inhibition in c-Met-driven tumors while reducing unwanted off-target toxicities due to activation of multiple kinases. Nonselective drugs can instead be considered in tumors that also recognize other drivers (e.g., ALK, ROS, VEGF). Improved understanding of the clinical pharmacokinetics of c-Met inhibitors can help avoid drug-drug interactions and optimize schedules for continuous in vivo inhibition of c-Met phosphorylation. The current review article provides a detailed overview of the clinical pharmacology of molecules used in c-Met-driven tumors., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Histone deacetylases (HDACs) play crucial roles in cancers, but the role and mechanism of HDAC7 in NSCLC have not been fully understood., Methods: A total of 319 patients with non-small cell lung cancer (NSCLC) who underwent surgery were enrolled in this study. Immunohistochemistry and Kaplan-Meier survival analysis were performed to investigate the relationship between HDAC7, fibroblast growth factor 18 (FGF18) expression, and clinicopathologic characteristics. Cell functional experiments were implemented both in vivo and in vitro to investigate the effects on NSCLC cell proliferation and metastasis. Recombinant lentivirus-meditated in vivo gene overexpression or knockdown, real-time polymerase chain reaction (PCR), western blotting, and coimmunoprecipitation assays were applied to clarify the underlying molecular mechanism of HDAC7 in promoting NSCLC progression., Results: The elevated expression of HDAC7 or FGF18 was positively correlated with poor prognosis, tumor-node-metastasis (TNM) stage, and tumor differentiation of NSCLC patients. NSCLC patients with co-expressed HDAC7 and FGF18 suffered the worst prognosis. HDAC7 overexpression promoted NSCLC proliferation and metastasis by upregulating FGF18. Conversely, overexpression of FGF18 reversed the attenuated ability in tumor growth and metastasis mediated by downregulating HDAC7. In terms of mechanism, our results suggested that the interaction of HDAC7 with β-catenin caused decreased β-catenin acetylation level at Lys49 and decreased phosphorylation level at Ser45. As a consequence, the HDAC7-mediated posttranslational modification of β-catenin facilitated nuclear transfer and activated FGF18 expression via binding to TCF4. Furthermore, deubiquitinase USP10 interacted with and stabilized HDAC7. The suppression of USP10 significantly accelerated the degradation of HDAC7 and weakened NSCLC growth and migration., Conclusions: Our findings reveal that HDAC7 promotes NSCLC progression through being stabilized by USP10 and activating the β-catenin-FGF18 pathway. Targeting this novel pathway may be a promising strategy for further developments in NSCLC therapy., (© 2022. The Author(s).)

The advent of high-throughput sequencing has allowed to profoundly interrogate the molecular landscape of non-small cell lung cancer (NSCLC) in the last years. These findings constitute the opportunity to better stratify these patients in order to address specific treatments to well-defined oncogene-restricted subgroups. Among them, BRAF-mutated lung cancers represent around 4% of NSCLC, thus identifying a clinically relevant population that should be aptly managed. Pivotal phase II trials have demonstrated the efficacy of combinatorial treatment - dabrafenib plus trametinib, targeting both BRAF and MEK - for patients harboring V600E mutations, making this specific BRAF alteration a mandatory requirement in the genetic portrait of advanced non-squamous lung cancer patients. However, around half of BRAF+ NSCLC patients remain orphan of targeted approaches. Here we review the available evidence, mainly from a clinical perspective, of therapeutic strategies for both V600E and non-V600 patients, in terms of small molecule, immune checkpoint inhibitors and forthcoming integrated strategies. Looking at on-going clinical trials, a special attention is dedicated to emergent molecules and combinatorial strategies that not only will improve outcomes of classical V600E, but also will make concrete the chance of tailored treatments for the majority of BRAF-mutated patients., (Copyright © 2021 Elsevier Ltd. All rights reserved.)