KRAS Mutations in Solid Tumors: Characteristics, Current Therapeutic Strategy, and Potential Treatment Exploration

Abstract

Kristen rat sarcoma (KRAS) gene is one of the most common mutated oncogenes in solid tumors. Yet, KRAS inhibitors did not follow suit with the development of targeted therapy, for the structure of KRAS has been considered as being implausible to target for decades. Chemotherapy was the initial recommended therapy for KRAS-mutant cancer patients, which was then replaced by or combined with immunotherapy. KRAS G12C inhibitors became the most recent breakthrough in targeted therapy, with Sotorasib being approved by the Food and Drug Administration (FDA) based on its significant efficacy in multiple clinical studies. However, the subtypes of the KRAS mutations are complex, and the development of inhibitors targeting non-G12C subtypes is still at a relatively early stage. In addition, the monotherapy of KRAS inhibitors has accumulated possible resistance, acquiring the exploration of combination therapies or next-generation KRAS inhibitors. Thus, other non-target, conventional therapies have also been considered as being promising. Here in this review, we went through the characteristics of KRAS mutations in cancer patients, and the prognostic effect that it poses on different therapies and advanced therapeutic strategy, as well as cutting-edge research on the mechanisms of drug resistance, tumor development, and the immune microenvironment.

Keywords: KRAS mutations; drug resistance; immune microenvironment; oncogenic mechanisms; therapeutic strategy.

Figure 1

Signaling Pathways Related to KRAS Mutations, and Potential Treatment Strategies. * KRAS switches between a guanosine diphosphate (GDP)-bound inactive state and a guanosine triphosphate (GTP)-bound active state. Normally, KRAS is bound to GDP and remains inactive. Activation through receptor tyrosine kinases (RTKs) leads to the activation of the guanine nucleotide exchange factor (GEF) family, which subsequently triggers the exchange between GDP and GTP. GTP-bound active KRAS transduces downstream signals, including mitogen-activated protein kinase (MAPK) pathway and the phosphoinositide 3-kinase (PI3K) pathway, which are responsible for cell proliferation, cell cycle regulation, cell survival, and cell differentiation. The treatment approaches of KRAS mutant patients include therapies targeting KRAS, and factors involved in the KRAS mutation pathways, such as RTKs, SHP2, PI3K pathway elements, MAPK pathway elements, and CDK4/6. ICIs are also included, considering the potential effect on KRAS mutant patients. This figure was created using Figdraw.