Stratification of patients with KRAS-mutated advanced non-small cell lung cancer: improving prognostics

ABSTRACTIntroduction KRAS is the most frequently mutated oncogene in cancer and encodes a key signaling protein in tumors. Due to its high affinity for GTP and the lack of a large binding pocket that allosteric inhibitors can occupy, KRAS has long been considered ‘non-druggable.’ Finding effective treatment measures for patients with KRAS mutations is our top priority.Areas covered In this article, we will provide an overview of the KRAS pathway and review the current state of therapeutic strategies for targeting oncogenic KRAS, as well as their potential to improve outcomes in patients with KRAS-mutant malignancies. We will also discuss the development of these strategies and gave an outlook on prospects.Expert opinion KRAS mutations have posed a significant challenge in the treatment of advanced non-small cell lung cancer (NSCLC) over the past few decades. However, the emergence of immunotherapy and KRAS inhibitors, such as Sotorasib (AMG 510) and Adagrasib (MRTX849), has marked a new era in cancer therapy. As more research and clinical trials continue, we anticipate the development of more effective treatment strategies and better options for lung cancer patients.KEYWORDS: KRAS mutation; lung cancerImmunotherapyTargeted therapySotorasibAdagrasibDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. Declaration of interestThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to discloseArticle highlightsKRAS is the most common oncogenic protein insolid tumors and was once considered a ”non-druggable” target.KRAS G12C is the most common KRAS mutationin NSCLC patients, while KRAS G12D and KRAS G12V are the most common mutationsin colorectal and pancreatic cancerSotorasib and Adagrasib are recommended assecond-line treatment options for patients with advanced KRAS-mutant NSCLCafter experiencing treatment failure with first-line therapy.Additional informationFundingThis work received financial support from the Natural Science Foundation of Hunan Province (grant numbers: 2021RC4040, 2023JJ30371 and 2023JJ30368). The funding agencies had no role in the study design, data collection, analysis, interpretation, manuscript writing, and decision to submit the article for publication.