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Introduction Lung cancer has remained the leading cause of cancer death among both men and women, and it accounts for around one-fourth of all cancer deaths worldwide despite great efforts [...], Development of effective strategies to manage the inevitable acquired resistance to osimertinib, a third-generation EGFR inhibitor for the treatment of EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC), is urgently needed. This study reports that DNA topoisomerase II (Topo II) inhibitors, doxorubicin and etoposide, synergistically decreased cell survival, with enhanced induction of DNA damage and apoptosis in osimertinib-resistant cells; suppressed the growth of osimertinib-resistant tumors; and delayed the emergence of osimertinib-acquired resistance. Mechanistically, osimertinib decreased Topo II[alpha] levels in EGFRm NSCLC cells by facilitating FBXW7-mediated proteasomal degradation, resulting in induction of DNA damage; these effects were lost in osimertinib-resistant cell lines that possess elevated levels of Topo II[alpha]. Increased Topo II[alpha] levels were also detected in the majority of tissue samples from patients with NSCLC after relapse from EGFR tyrosine kinase inhibitor treatment. Enforced expression of an ectopic TOP2A gene in sensitive EGFRm NSCLC cells conferred resistance to osimertinib, whereas knockdown of TOP2A in osimertinib-resistant cell lines restored their susceptibility to osimertinib-induced DNA damage and apoptosis. Together, these results reveal an essential role of Topo II[alpha] inhibition in mediating the therapeutic efficacy of osimertinib against EGFRm NSCLC, providing scientific rationale for targeting Topo II to manage acquired resistance to osimertinib.

Background: Ras-GTPase-activating protein (GAP)-binding protein 1 (G3BP1) emerges as a pivotal oncogenic gene across various malignancies, notably including nasopharyngeal carcinoma (NPC). The use of automated image analysis tools for immunohistochemical (IHC) staining of particular proteins is highly beneficial, as it could reduce the burden on pathologists. Interestingly, there have been no prior studies that have examined G3BP1 IHC staining using digital pathology. Methods: Whole-slide images (WSIs) were meticulously collected and annotated by experienced pathologists. A model was intricately designed and rigorously tested to yield the quantitative data regarding staining intensity and extent. The collective output data was subjected multiplicative analysis, exploring its correlation with the prognosis. Results: The G3BP1 molecular marker scoring model was successfully established utilizing deep learning methodologies, with a calculated threshold staining scores of 1.5. Notably, patients with NPC exhibiting higher expression levels of G3BP1 proteins displayed significantly lower for overall survival rates (OS). Multivariate analysis further validated that positive expression of G3BP1 stood as an independent poorer prognostic factors, indicating a poorer prognosis for NPC patients. Conclusion: Computational pathology emerges as a transformative tool capable of substantially reducing the burden on pathologists while concurrently enhancing and diagnostic sensitivity and specificity. The positive expression of G3BP1 protein serves as valuable, independent biomarker, offering predictive insights into a poor prognosis for patients with NPC. [ABSTRACT FROM AUTHOR]

MicroRNA (miRNA) dysregulation has been identified in several carcinomas, including non-small cell lung cancer (NSCLC), and is known to play a role in the development and progression of this disease. We initially conducted a miRNA microarray analysis, which revealed that the MNK inhibitor CGP57380 increased the expression of miR-150-3p. A similar analysis was performed using data from The Cancer Genome Atlas (TCGA). Cell proliferation, colony formation and migration assays were validated in A549 and H157 cells treated with miR-150-3p mimics. Quantitative polymerase chain reaction (qPCR) was then used to detect potential target genes. We observed significant downregulation of miR-150-3p in NSCLC samples compared with normal samples (P = 0.035). High miR-150-3p expression was associated with longer overall survival (P = 0.005), as determined via a tissue microarray (TMA). These results were validated in the TCGA and revealed that miR-150-3p was expressed at low levels in NSCLC tissues (P < 0.0001) and that patients with high miR-150-3p expression had a better prognosis (P = 0.042). Moreover, the combination of miR-150-3p and CGP57380 exerted a synergistic inhibitory effect on colony formation, growth, and migration and induced apoptosis in NSCLC cell lines. We investigated the potential targets of miR-150-3p and successfully validated six potential target genes through qPCR analysis. High miR-150-3p expression may enhance the response to immunotherapy, cisplatin and gemcitabine. In summary, this study underscores the promising therapeutic implications of combining miR-150-3p and CGP57380 for NSCLC treatment. Additionally, this study provides valuable insights into the molecular mechanisms underlying the effects of this treatment. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) is a prevalent malignancy in China, commonly associated with undifferentiated cell types and Epstein-Barr virus (EBV) infection. The presence of intense lymphocytic infiltration and elevated expression of programmed cell death ligand 1(PD-L1) in NPC highlights its potential for immunotherapy, yet current treatment outcomes remain suboptimal. In this review, we explore the tumor microenvironment of NPC to better understand the mechanisms of resistance to immunotherapy, evaluate current therapeutic strategies, and pinpoint emerging targets, such as tertiary lymphoid structures (TLSs), that could enhance treatment outcomes and prognostic accuracy. TLSs have demonstrated positive prognostic value in NPC, making them a promising target for future therapies. This review summarizes the key characteristics of TLSs and latest research in the context of NPC. We are optimistic that targeting TLSs could improve immunotherapy outcomes for NPC patients, ultimately leading to more effective treatment strategies and better patient survival. [ABSTRACT FROM AUTHOR]

There is an urgent need to fully understand the biology of third generation EGFR‐tyrosine kinase inhibitors (EGFR‐TKIs), particularly osimertinib, and to develop mechanism‐driven strategies to manage their acquired resistance. Transient receptor potential melastatin‐2 (TRPM2) functions as an important regulator of Ca2+ influx, but its role in mediating therapeutic efficacies of EGFR‐TKIs and acquired resistance to EGFR‐TKIs has been rarely studied. This study has demonstrated a previously undiscovered role of suppression of TRPM2 and subsequent inhibition of Ca2+ influx and induction of ROS and DNA damage in mediating apoptosis induction and the therapeutic efficacy of osimertinib against EGFR mutant NSCLC. The rebound elevation represents a key mechanism accounting for the emergence of acquired resistance to osimertinib and other third generation EGFR‐TKIs. Accordingly, targeting TRPM2 is a potentially promising strategy for overcoming and preventing acquired resistance to osimertinib, warranting further study in this direction including the development of cancer therapy‐optimized TRPM2 inhibitors. [ABSTRACT FROM AUTHOR]

Breast cancer is the most prevalent malignancy and the most significant contributor to mortality in female oncology patients. Potassium Two Pore Domain Channel Subfamily K Member 1 (KCNK1) is differentially expressed in a variety of tumors, but the mechanism of its function in breast cancer is unknown. In this study, we found for the first time that KCNK1 was significantly up-regulated in human breast cancer and was correlated with poor prognosis in breast cancer patients. KCNK1 promoted breast cancer proliferation, invasion, and metastasis in vitro and vivo. Further studies unexpectedly revealed that KCNK1 increased the glycolysis and lactate production in breast cancer cells by binding to and activating lactate dehydrogenase A (LDHA), which promoted histones lysine lactylation to induce the expression of a series of downstream genes and LDHA itself. Notably, increased expression of LDHA served as a vicious positive feedback to reduce tumor cell stiffness and adhesion, which eventually resulted in the proliferation, invasion, and metastasis of breast cancer. In conclusion, our results suggest that KCNK1 may serve as a potential breast cancer biomarker, and deeper insight into the cancer-promoting mechanism of KCNK1 may uncover a novel therapeutic target for breast cancer treatment. KCNK1 is a potassium channel differentially expressed in many tumors, but the mechanisms underlying its function in breast cancer remain unclear. This study shows that KCNK1 is overexpressed in breast cancer promoting proliferation, invasion and metastasis by increasing glycolysis and activating Lactate Dehydrogenase A. [ABSTRACT FROM AUTHOR]

BRD7 was identified as a tumor suppressor in nasopharyngeal carcinoma (NPC). Circular RNAs (CircRNAs) are involved in the occurrence and development of NPC as oncogenes or tumor suppressors. However, the function and mechanism of the circular RNA forms derived from BRD7 in NPC are not well understood. In this study, we first identified that circBRD7 was a novel circRNA derived from BRD7 that inhibited cell proliferation, migration, invasion of NPC cells, as well as the xenograft tumor growth and metastasis in vivo. Mechanistically, circBRD7 promoted the transcriptional activation and expression of BRD7 by enhancing the enrichment of histone 3 lysine 27 acetylation (H3K27ac) in the promoter region of its host gene BRD7, and BRD7 promoted the formation of circBRD7. Therefore, circBRD7 formed a positive feedback loop with BRD7 to inhibit NPC development and progression. Moreover, restoration of BRD7 expression rescued the inhibitory effect of circBRD7 on the malignant progression of NPC. In addition, circBRD7 demonstrated low expression in NPC tissues, which was positively correlated with BRD7 expression and negatively correlated with the clinical stage of NPC patients. Taken together, circBRD7 attenuates the tumor growth and metastasis of NPC by forming a positive feedback loop with its host gene BRD7, and targeting the circBRD7/BRD7 axis is a promising strategy for the clinical diagnosis and treatment of NPC. [ABSTRACT FROM AUTHOR]