Recently approved and highly specific small-molecule inhibitors of c-MET exon 14 skipping mutations (e.g., capmatinib, tepotinib) are a new and important therapeutic option for the treatment of non-small cell lung cancer (NSCLC) patients harbouring c-MET alterations. Several experimental studies have provided compelling evidence that c-MET is involved in the regulation of the immune response by up-regulating inhibitory molecules (e.g., PD-L1) and down-regulating of immune stimulators (e.g., CD137, CD252, CD70, etc.). In addition, c-MET was found to be implicated in the regulation of the inflamed tumour microenvironment (TME) and thereby contributing to an increased immune escape of tumour cells from T cell killing. Moreover, it is a major resistance mechanism following treatment of epidermal growth factor receptor mutations (EGFRmut) with tyrosine kinase receptor inhibitors (TKIs). In line with these findings c-MET alterations have also been shown to be associated with a worse clinical outcome and a poorer prognosis in NSCLC patients. However, the underlying mechanisms for these experimental observations are neither fully evaluated nor conclusive, but clearly multifactorial and most likely tumour-specific. In this regard the clinical efficacy of checkpoint inhibitors (CPIs) and TKIs against EGFRmut in NSCLC patients harbouring c-MET alterations is also not yet established, and further research will certainly provide some guidance as to optimally utilise CPIs and c-MET inhibitors in the future.
Keywords: Programmed cell death ligand-1 (PD-1); c-MET; epidermal growth factor receptor mutations (EGFRmut); immunotherapy resistance; non-small cell lung cancer (NSCLC).
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