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.
Highlights
Using an oversimplified description, cancer could be defined as a disease caused by the accumulation of alterations in genes coding for proteins involved in cell growth induction or control defined oncogenes or tumor suppressor genes, respectively
KRAS mutations are involved in the pathogenesis of different epithelial cancer histotypes, including lung and colorectal cancer, but its role has been especially investigated in pancreatic ductal adenocarcinoma, which is considered the type of tumor mostly dependent on KRAS for its development, metastatic progression, and treatment resistance [2,3,4,5]
Whereas KRASG12C mutations are frequent in lung adenocarcinoma, they are rare in pancreatic ductal adenocarcinoma (PDAC)
Summary
Cancer could be defined as a disease caused by the accumulation of alterations in genes coding for proteins involved in cell growth induction or control defined oncogenes or tumor suppressor genes, respectively. The most important successes in cancer treatment have been, KRAS in Epithelial Cancers represented by experimental therapeutics able to effectively interfere with the product of some of the most relevant oncogenes in human cancers In this regard, those human cancers for which the development of appropriate targeted therapeutics has been most frustrating are sustained in their proliferation by altered genes whose function is essential for the integration and the transduction of physiologic signals in normal cells. KRAS mutated cancer cells carry mostly missense mutations causing single amino-acid substitutions in three hotspots, glycine (G12), glycine (G13), and glutamine (Q61) These mutations prevent GAPs from accessing GTP so that hydrolysis is blocked, resulting in a persistently activated GTP-bound state. KRASG12D mutation enhances membrane and adherens junction signaling, while KRASG13Dactivates signaling molecules such as MAPK kinases, non-receptor tyrosine kinases, and regulators of metabolic processes [9]
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