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.

Mesonephric-like Adenocarcinoma of the Female Genital Tract – Possible Role of KRAS-targeted Treatment: Detailed Molecular Analysis of a Case Series and Review of the Literature for targetable somatic KRAS -Mutations

“…The Kristen rat sarcoma (KRAS) gene is one of the most common mutational alterations in solid tumors [Yang et al 2023] and occurs in approximately 22% [Forbes et al 2011].…”

Mesonephric-like adenocarcinoma of the female genital tract: possible role of KRAS-targeted treatment—detailed molecular analysis of a case series and review of the literature for targetable somatic KRAS-mutations

“…The Kristen rat sarcoma ( KRAS ) gene is one of the most common mutational alterations in solid tumors (Yang et al 2023 ) and occurs in approximately 22% (Forbes et al 2011 ).…”

“…Recently, targeted inhibitors of KRAS have offered a breakthrough for solid tumors (Yang et al 2023 ; Skoulidis et al 2021 ; Fakih et al 2022 ; Strickler et al 2023 ; Hong et al 2020 ). Sotarasib is a specific and irreversible inhibitor of the GTPase-protein in p.G12C- KRAS -mutated cancers.…”

Biological insights in non-small cell lung cancer

“…HGF has been reported to confer resistance to EGFR TKIs by inducing interceptor cross talk with integrin β4 (ITGβ4), EphA2, CCDP1, AXL, and JAK 94 . Multiple drugs have been developed to directly target KRAS G12C, among which the most well-known are sotorasib (AMG510) and adagrasib (MRTX849); however, many other direct oral inhibitors of KRAS are emerging 53 , 95 , such as GFH925 95 . A first-line trial combining GFH925 plus cetuximab in treating metastatic NSCLC (NCT05756153) is expected to provide further insights into the potential benefits of this combination therapy, and to alert researchers to potential putative mechanisms of resistance that may arise, probably those associated with KRAS G12C amplification.…”