Targeting KRAS: The Elephant in the Room of Epithelial Cancers

Abstract

Mutations of the proto-oncogene KRAS are the most frequent gain-of-function alterations found in cancer. KRAS is mutated in about 30% of all human tumors, but it could reach more than 90% in certain cancer types such as pancreatic adenocarcinoma. Although historically considered to be undruggable, a particular KRAS mutation, the G12C variant, has recently emerged as an actionable alteration especially in non-small cell lung cancer (NSCLC). KRASG12C and pan-KRAS inhibitors are being tested in clinical trials and have recently shown promising activity. Due to the difficulties in direct targeting of KRAS, other approaches are being explored. The inhibition of target upstream activators or downstream effectors of KRAS pathway has shown to be moderately effective given the evidence of emerging mechanisms of resistance. Various synthetic lethal partners of KRAS have recently being identified and the inhibition of some of those might prove to be successful in the future. The study of escape mechanisms to KRAS inhibition could support the utility of combination strategies in overcoming intrinsic and adaptive resistance and enhancing clinical benefit of KRASG12C inhibitors. Considering the role of the microenvironment in influencing tumor initiation and promotion, the immune tumor niche of KRAS mutant tumors has been deeply explored and characterized for its unique immunosuppressive skewing. However, a number of aspects remains to be fully understood, and modulating this tumor niche might revert the immunoresistance of KRAS mutant tumors. Synergistic associations of KRASG12C and immune checkpoint inhibitors are being tested.

m6A Methylation Modification Patterns and Tumor Microenvironment Infiltration Characterization in Pancreatic Cancer

“…An important feature of KRAS mutant tumors is the immunosuppressive state ( 40 ). KRAS signaling induces the expression of immune regulatory factors and inflammatory cytokines in tumor cells, and subsequently recruits neutrophils and myeloid-derived suppressor cells (MDSC) to form an immunosuppressive tumor microenvironment ( 41 ). Mutated KRAS in pancreatic cancer plays a central role in tumor development and growth by regulating T-cell cytokines in TME.…”

Prognostic Value of Drug Targets Predicted using Deep Bioinformatic Analysis of M6A-associated lncRNA-based Pancreatic Cancer Model Characteristics and its Tumour Microenvironment

“…In addition, immunosuppression in the TME is related to mutations in KRAS. A related study [31] showed that mutations in the TP53 gene are common in tumours and affect the recruitment and activity of T cells, thus also leading to immune evasion [32] . These m6A-associated lncRNA gene mutations are closely associated with immune activity in the TME, suggesting an interaction between m6A modi cations and tumour immunogenomics.…”

Resectable and Borderline Resectable Pancreatic Ductal Adenocarcinoma: Role of the Radiologist and Oncologist in the Era of Precision Medicine

“…Recently, germline BRCA mutations have been validated as a predictive factor of response to the PARP inhibitor olaparib after platinum-based chemotherapy in the metastatic setting [85]. Other therapeutic targets that are being investigated in advanced disease include homologous recombination repair deficiency (HRD), microsatellite instability, HER2/HER3, CDK4/6, NTRK fusions, KRAS G12C, and BRAF mutations [83,86,87].…”