Abstract
Non-small cell lung cancer (NSCLC) patients with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation are associated with significant clinical heterogeneity and a poor prognosis to standard NSCLC therapies such as surgical resection, radiotherapy, chemotherapies, and targeted medicines. However, the application of immune checkpoints inhibitors (ICIs) has dramatically altered the therapeutic pattern of NSCLC management. Clinical studies have indicated that some KRAS-mutant NSCLC patients could benefit from ICIs; however, the responses in some patients are still poor. This review intends to elucidate the mechanisms of resistance to immunotherapy in KRAS-driven NSCLC and highlight the TME functions altered by immunoinhibitors, immunostimulators, and cancer metabolism. These metabolic pathways could potentially be promising approaches to overcome immunotherapy resistance.
Highlights
Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related deaths worldwide[1]
We summarize and analyze the possible mechanisms underlying the resistance to immune checkpoints inhibitors (ICIs) in non-small cell lung cancer (NSCLC) with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation and mainly focus on the role of the tumor microenvironment (TME) and metabolism, therapeutic implications, and potential targets for overcoming the resistance to or improving the efficacy of ICIs treatments in KRASmutant NSCLC
It has been reported that the development of resistance to anti-programmed cell death ligand 1 (PD-L1) and mitogen-activated protein kinase kinase 1 (MEK) inhibition is the result of increasing IL-17 and IL-22 secreted by accumulated infiltration of Th17 in KRASmut/tumor protein 53 (TP53)-/- co-mutant lung cancer patients[41]
Summary
Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related deaths worldwide[1]. Since KRAS mutation is reported to be associated with resistance to multiple therapies and poor prognosis in NSCLC, several preclinical and clinical studies have investigated effective therapies, including immunotherapy and targeted therapy[6,7]. Controversial results have been reported in multiple clinical studies on the efficacy of immune checkpoints inhibitors (ICIs) in NSCLC with KRAS mutation[12,13,14,15].
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