Targeting MERTK and AXL in EGFR Mutant Non-Small Cell Lung Cancer

MERTK and AXL are members of the TAM family of receptor tyrosine kinases and are abnormally expressed in 69% and 93% of non-small cell lung cancers (NSCLCs), respectively. Expression of MERTK and/or AXL provides a survival advantage for NSCLC cells and correlates with lymph node metastasis, drug resistance, and disease progression in patients with NSCLC. The TAM receptors on host tumor infiltrating cells also play important roles in the immunosuppressive tumor microenvironment. Thus, MERTK and AXL are attractive biologic targets for NSCLC treatment. Here, we will review physiologic and oncologic roles for MERTK and AXL with an emphasis on the potential to target these kinases in NSCLCs with activating EGFR mutations.

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Emerging Molecular Dependencies of Mutant EGFR-Driven Non-Small Cell Lung Cancer

Cells ◽

10.3390/cells10123553 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3553

Author(s):

Dylan A. Farnsworth ◽

Yankuan T. Chen ◽

Georgia de Rappard Yuswack ◽

William W. Lockwood

Keyword(s):

Molecular Mechanisms ◽

Kinase Inhibitors ◽

Growth Factor Receptor ◽

Small Cell ◽

Egfr Mutations ◽

Small Cell Lung ◽

Lung Cancers ◽

Egfr Mutant ◽

Successive Generations ◽

Mutant Egfr

Epidermal growth factor receptor (EGFR) mutations are the molecular driver of a subset of non-small cell lung cancers (NSCLC); tumors that harbor these mutations are often dependent on sustained oncogene signaling for survival, a concept known as “oncogene addiction”. Inhibiting EGFR with tyrosine kinase inhibitors has improved clinical outcomes for patients; however, successive generations of inhibitors have failed to prevent the eventual emergence of resistance to targeted agents. Although these tumors have a well-established dependency on EGFR signaling, there remain questions about the underlying genetic mechanisms necessary for EGFR-driven oncogenesis and the factors that allow tumor cells to escape EGFR dependence. In this review, we highlight the latest findings on mutant EGFR dependencies, co-operative drivers, and molecular mechanisms that underlie sensitivity to EGFR inhibitors. Additionally, we offer perspective on how these discoveries may inform novel combination therapies tailored to EGFR mutant NSCLC.

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Role of Survivin in EGFR Inhibitor–Induced Apoptosis in Non–Small Cell Lung Cancers Positive for EGFR Mutations

Cancer Research ◽

10.1158/0008-5472.can-10-2438 ◽

2010 ◽

Vol 70 (24) ◽

pp. 10402-10410 ◽

Cited By ~ 55

Author(s):

Kunio Okamoto ◽

Isamu Okamoto ◽

Wataru Okamoto ◽

Kaoru Tanaka ◽

Ken Takezawa ◽

...

Keyword(s):

Small Cell ◽

Egfr Mutations ◽

Egfr Inhibitor ◽

Small Cell Lung ◽

Lung Cancers ◽

Induced Apoptosis

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Concomitance of P-gp/LRP Expression with EGFR Mutations in Exons 19 and 21 in Non-Small Cell Lung Cancers

Yonsei Medical Journal ◽

10.3349/ymj.2016.57.1.50 ◽

2016 ◽

Vol 57 (1) ◽

pp. 50 ◽

Cited By ~ 8

Author(s):

Hong Wei ◽

Weipeng Lu ◽

Mei Li ◽

Qiuping Zhang ◽

Shen Lu

Keyword(s):

Small Cell ◽

Egfr Mutations ◽

Small Cell Lung ◽

Lung Cancers

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Concurrent Genetic Alterations and Other Biomarkers Predict Treatment Efficacy of EGFR-TKIs in EGFR-Mutant Non-Small Cell Lung Cancer: A Review

Frontiers in Oncology ◽

10.3389/fonc.2020.610923 ◽

2020 ◽

Vol 10 ◽

Author(s):

Yijia Guo ◽

Jun Song ◽

Yanru Wang ◽

Letian Huang ◽

Li Sun ◽

...

Keyword(s):

Lung Cancer ◽

Treatment Efficacy ◽

Genetic Alterations ◽

Small Cell ◽

Egfr Mutations ◽

Small Cell Lung ◽

Egfr Mutant ◽

Egfr Tki ◽

Egfr Tkis ◽

Gene Alterations

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) greatly improve the survival and quality of life of non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, many patients exhibit de novo or primary/early resistance. In addition, patients who initially respond to EGFR-TKIs exhibit marked diversity in clinical outcomes. With the development of comprehensive genomic profiling, various mutations and concurrent (i.e., coexisting) genetic alterations have been discovered. Many studies have revealed that concurrent genetic alterations play an important role in the response and resistance of EGFR-mutant NSCLC to EGFR-TKIs. To optimize clinical outcomes, a better understanding of specific concurrent gene alterations and their impact on EGFR-TKI treatment efficacy is necessary. Further exploration of other biomarkers that can predict EGFR-TKI efficacy will help clinicians identify patients who may not respond to TKIs and allow them to choose appropriate treatment strategies. Here, we review the literature on specific gene alterations that coexist with EGFR mutations, including common alterations (intra-EGFR [on target] co-mutation, TP53, PIK3CA, and PTEN) and driver gene alterations (ALK, KRAS, ROS1, and MET). We also summarize data for other biomarkers (e.g., PD-L1 expression and BIM polymorphisms) associated with EGFR-TKI efficacy.

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Molecular Profiling and the Reclassification of Cancer: Divide and Conquer

American Society of Clinical Oncology Educational Book ◽

10.14694/edbook_am.2013.33.127 ◽

2013 ◽

pp. 127-134 ◽

Cited By ~ 3

Author(s):

Javier Munoz ◽

Charles Swanton ◽

Razelle Kurzrock

Keyword(s):

Growth Factor Receptor ◽

Molecular Profiling ◽

Small Cell ◽

Divide And Conquer ◽

Egfr Mutations ◽

Diagnostic Process ◽

Small Cell Lung ◽

Lung Cancers ◽

The Right ◽

Molecular Aberrations

Cancer is one of the leading causes of mortality in the world. Choosing the best treatment is dependent on making the right diagnosis. The diagnostic process has been based on light microscopy and the identification of the organ of tumor origin. Yet we now know that cancer is driven by molecular processes, and that these do not necessarily segregate by organ of origin. Fortunately, revolutionary changes in technology have enabled rapid genomic profiling. It is now apparent that neoplasms classified uniformly (e.g., non-small cell lung cancer) are actually comprised of up to 100 different molecular entities. For instance, tumors bearing ALK alterations make up about 4% of non-small cell lung cancers, and tumors bearing epidermal growth factor receptor (EGFR) mutations, approximately 5% to 10%. Importantly, matching patients to therapies targeted against their driver molecular aberrations has resulted in remarkable response rates. There is now a wealth of evidence supporting a divide-and-conquer strategy. Herein, we provide a concise primer on the current state-of-the-art of molecular profiling in the cancer clinic.

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Application of immune checkpoint inhibitors in EGFR-mutant non-small-cell lung cancer: from bed to bench

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920930333 ◽

2020 ◽

Vol 12 ◽

pp. 175883592093033

Author(s):

Rui Jin ◽

Jing Zhao ◽

Lexin Xia ◽

Qin Li ◽

Wen Li ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Targeted Therapies ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Small Cell ◽

Egfr Mutations ◽

Small Cell Lung ◽

Egfr Mutant

Targeted therapies are efficient in the context of oncogenic driver mutations. Epidermal growth factor receptor (EGFR)-mutant lung cancers represent a distinct subset of non-small-cell lung cancer (NSCLC) with marked sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Despite the high response rate to EGFR TKIs in EGFR-mutant lung cancer, resistance and tumor recurrence are unavoidable. Therapeutic options are restricted in patients after exhaustion of targeted therapies. Immune checkpoint inhibitors (ICIs) represent a novel therapeutic option for advanced NSCLC with significant overall survival benefit in registration trials. No superiority in terms of long-term survival was observed in the EGFR mutation subgroup when ICIs were given as monotherapy in second-line treatment in earlier studies. Thus, the appropriate application of ICIs to patients harboring EGFR mutations remains an important field of ongoing research. Here, we discuss different immune checkpoint blockade strategies, including ICIs alone and in combination with TKIs, chemotherapy, radiation, and antiangiogenic agents in EGFR-mutant NSCLC as first-line and subsequent treatments. We also summarize the evidence concerning the heterogeneous molecular features and immune signatures of EGFR mutations and their associations with ICI therapy outcomes. This study was performed to improve our understanding of the optimal mode of immune-based treatment approaches in EGFR-mutant NSCLC.

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Pulmonary Lymphoepithelioma-like Carcinoma

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2018-0149-rs ◽

2019 ◽

Vol 143 (8) ◽

pp. 1027-1030 ◽

Cited By ~ 5

Author(s):

Sakda Sathirareuangchai ◽

Kirk Hirata

Keyword(s):

Tumor Cells ◽

Pulmonary Involvement ◽

Undifferentiated Carcinoma ◽

Small Cell ◽

Egfr Mutations ◽

Small Cell Lung ◽

Rare Type ◽

Lung Cancers ◽

Barr Virus ◽

Asian Populations

Pulmonary lymphoepithelioma-like carcinoma is a rare type of non–small cell lung cancer. The tumor is usually discovered in young, nonsmoking Asian populations. The patients are diagnosed at an earlier stage and have a better prognosis than those with other non–small cell lung cancers. Histologically, the tumor morphology is indistinguishable from undifferentiated carcinoma of the nasopharynx. It is characterized by nests or diffuse sheets of syncytial tumor cells, which show round to oval vesicular nuclei with prominent nucleoli, along with an admixed heavy lymphocytic and plasma cell infiltrate. The presence of Epstein-Barr virus in the tumor cells is crucial for the diagnosis. The differential diagnoses include lymphoepithelioma-like carcinoma from other sites and pulmonary involvement of lymphoma. EGFR mutations and ALK rearrangements are not commonly found in lymphoepithelioma-like carcinoma, in contrast to programmed death ligand-1 expression, which is shown in a majority of cases.

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