Abstract
Simple SummaryExpression of MERTK and/or AXL (members of the TAM family of receptor tyrosine kinases) provides a survival advantage for non-small cell lung cancer (NSCLC) cells and correlates with lymph node metastasis, drug resistance, and disease progression. 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, and clinical trials have recently been launched exploring the efficacy of MERTK/AXL inhibitors in NSCLC. This timely review will address the potential clinical impact of these agents as well as potential side effects to be monitored with the use of these novel drugs.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.
Highlights
Despite intensive efforts over many years, lung cancer remains difficult to treat and is still the leading cause of cancer-related death in both men and women worldwide
Oncogenic drivers, epidermal growth factor receptor (EGFR) [15,16,17,18] and anaplastic lymphoma kinase (ALK) [19,20,21], molecular-targeted therapies have been applied to the management of metastatic non-small cell lung cancers (NSCLCs), resulting in remarkably improved prognosis and quality of life relative to patients treated with conventional chemotherapeutics [22,23,24]
Expression of MERTK and AXL on tumor-infiltrating macrophages polarizes them towards a pro-tumor M2-like phenotype [143,144,145,146]
Summary
Despite intensive efforts over many years, lung cancer remains difficult to treat and is still the leading cause of cancer-related death in both men and women worldwide. Following clinical validation of translational inhibitors targeting two important NSCLC oncogenic drivers, epidermal growth factor receptor (EGFR) [15,16,17,18] and anaplastic lymphoma kinase (ALK) [19,20,21], molecular-targeted therapies have been applied to the management of metastatic NSCLC, resulting in remarkably improved prognosis and quality of life relative to patients treated with conventional chemotherapeutics [22,23,24]. New therapeutic approaches will be required to further enhance outcomes. Both MERTK and AXL, members of the TAM (TYRO3, AXL, and MERTK) family of receptor tyrosine kinases (RTK), are emerging therapeutic targets in NSCLC. The potential to target MERTK and AXL in mtEGFR-expressing NSCLC to improve clinical outcomes will be discussed
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