Abstract
Epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) are currently the most effective treatment for non-small cell lung cancer (NSCLC) patients, who carry primary EGFR mutations. However, the patients eventually develop drug resistance to EGFR-TKIs after approximately one year. In addition to the acquisition of the EGFR T790M mutation, the activation of alternative receptor-mediated signaling pathways is a common mechanism for conferring the insensitivity of EGFR-TKI in NSCLC. Upregulation of the Mer receptor tyrosine kinase (MERTK), which is a member of the Tyro3-Axl-MERTK (TAM) family, is associated with a poor prognosis of many cancers. The binding of specific ligands, such as Gas6 and PROS1, to MERTK activates phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) cascades, which are the signaling pathways shared by EGFR. Therefore, the inhibition of MERTK can be considered a new therapeutic strategy for overcoming the resistance of NSCLC to EGFR-targeted agents. Although several small molecules and monoclonal antibodies targeting the TAM family are being developed and have been described to enhance the chemosensitivity and converse the resistance of EGFR-TKI, few have specifically been developed as MERTK inhibitors. The further development and investigation of biomarkers which can accurately predict MERTK activity and the response to MERTK inhibitors and MERTK-specific drugs are vitally important for obtaining appropriate patient stratification and increased benefits in clinical applications.
Highlights
Lung cancer remains the leading cause of cancer-related death worldwide, and nonsmall cell lung cancer (NSCLC) represents the major histological subtype of the disease [1,2].A subgroup of NSCLC patients, characterized by a high prevalence in never-smoker Asian females, respond well to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs), due to the presence of sensitizing EGFR mutations, including the L858R point mutation in exon 21 and exon 19 deletions [3,4]
The results in this study indicated that Mer receptor tyrosine kinase (MERTK) in the tumor microenvironment aids malignant tumor progression by suppressing antitumor immunity [79]
It has been shown that Yes-associated protein (YAP) is upregulated in EGFR-TKI-resistant lung adenocarcinoma [109], which may be mediated by an Akt and mitogen-activated protein kinase (MAPK)-independent phosphoinositide 3-kinase (PI3K)/PDK1 pathway [110]
Summary
Lung cancer remains the leading cause of cancer-related death worldwide, and nonsmall cell lung cancer (NSCLC) represents the major histological subtype of the disease [1,2]. The overactivation of other pro-survival receptor tyrosine kinases (RTKs), such as HER2 and MNNG HOS transforming gene (MET) that share similar downstream signaling pathways with EGFR, is frequently observed in EGFR-TKI-resistant patients without the EGFR T790M mutation [6,7]. Many experimental settings demonstrate that targeting the “bypass” RTKmediated signaling pathways is a potentially therapeutic strategy for overcoming the EGFR-TKI resistance Pharmaceuticals 2021, 14, 130 naling pathways with EGFR, is frequently observed in EGFR-TKI-resistant patients without the EGFR T790M mutation [6,7]. Alternative RTK-mediated signaling path(bypass) contribute to the of theof Through binding to their ligands, ways (bypass) contribute tosurvival the survival the EGFR-TKI-resistant cancer cells. Troduction of small molecules targeting MERTK that have therapeutic potential
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