Abstract
In non-small cell lung cancer (NSCLC), the most frequent oncogenic mutation in western countries is KRAS, for which, however, there remains no clinically approved targeted therapies. Recent progress on high biological heterogeneity including diverse KRAS point mutations, varying dependence on mutant KRAS, wide spectrum of other co-occurring genetic alterations, as well as distinct cellular status across the epithelial-to-mesenchymal transition (EMT), has not only deepened our understanding about the pathobiology of KRAS-mutant NSCLC but also brought about unprecedented new hopes for precision treatment of patients. In this review, we provide an update on the most recent advances in KRAS-mutant lung cancer, with a focus on mechanistic insights into tumor heterogeneity, the potential clinic implications and new therapies on horizons tailored for KRAS-mutant lung cancer.
Highlights
Lung cancer is the most common cancer with high lethality [1]
As a membrane-bound small GTPase, Kirsten rat sarcoma viral oncogene homolog (KRAS) switches between the active GTP-bound and inactive GDP-bound status, which is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), respectively [3]
Reactivation of GDP-bound RAS is mediated by GEFs, such as son of sevenless homolog 1 (SOS1), which promotes the release of bound GDP, and cellular GTP will replace GDP to bind to RAS
Summary
Carcinogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation is the most common gain-of-function alteration, accounting for ∼30% of lung adenocarcinomas in western countries and about 10% of Asian lung adenocarcinomas [2]. Considerable progress in developing molecularly-driven therapeutics has been made in the past decades, mainly including targeted therapies against oncogenic drivers, such as EGFR, HER2, EML4-ALK, MET, ROS1, and BRAF mutations, and immunotherapies in non-oncogene-driven lung cancer, such as PD1 and PDL1 alterations [5, 6]. We update the recent clinically relevant aspects of the pathobiology of KRAS-mutant non-small cell lung cancer (NSCLC), mainly focusing on tumor heterogeneity, therapeutic implications, and new treatment opportunities
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