Unveiling the role of KRAS in tumor immune microenvironment

• DOI: 10.1016/j.biopha.2023.116058
• Publication Date: 2024-01-02T12:19:03Z
• Authors: Miao Xu; Xing Zhao; Ti Wen; Xiujuan Qu
• Keywords: Immune checkpoint

Kirsten rats sarcoma viral oncogene (KRAS), the first discovered human oncogene, has long been recognized as "undruggable". KRAS mutations frequently occur in multiple cancers including non-small cell lung cancer(NSCLC), colorectal cancer(CRC) and pancreatic ductal adenocarcinoma(PDAC), functioning a "molecule switch" determining activation of various oncogenic signaling pathways. Except for its intrinsic pro-tumorigenic role, alteration also exhibits an unique immune signature characterized by elevated PD-L1 level high tumor mutational burden(TMB). mutation shape suppressive microenvironment impeding effective T cells infiltration recruiting myeloid-derived suppressor cells(MDSCs), regulatory cells(Tregs), cancer associated fibroblasts(CAFs). In checkpoint inhibitor(ICI) era, NSCLC patients with mutated tend to be more responsive ICI than intact KRAS. The hallmark is existence kinds co-mutations. Different types co-alterations have distinct microenvironment(TME) signatures responses ICI. TP53 co-mutation possess "hot" TME achieve higher response immunotherapy while other loss function correlated "colder" poor outcome ICI-based therapy. groundbreaking discovery G12C inhibitors significantly improved outcomes this subtype even though efficacy was limited patients. restore TME, creating opportunity combinations However, inevitable challenge drug resistance. Promising combination strategies such SHP2 approach deserve further exploration because their modulatory effect.