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Abstract
KRAS is the most frequently mutated oncogene in non-small cell lung cancers (NSCLC), with a frequency of around 30%, and encoding a GTPAse that cycles between active form (GTP-bound) to inactive form (GDP-bound). The KRAS mutations favor the active form with inhibition of GTPAse activity. KRAS mutations are often with poor response of EGFR targeted therapies. KRAS mutations are good predictive factor for immunotherapy. The lack of success with direct targeting of KRAS proteins, downstream inhibition of KRAS effector pathways, and other strategies contributed to a focus on developing mutation-specific KRAS inhibitors. KRAS p.G12C mutation is one of the most frequent KRAS mutation in NSCLC, especially in current and former smokers (over 40%), which occurs among approximately 12-14% of NSCLC tumors. The mutated cysteine resides next to a pocket (P2) of the switch II region, and P2 is present only in the inactive GDP-bound KRAS. Small molecules such as sotorasib are now the first targeted drugs for KRAS G12C mutation, preventing conversion of the mutant protein to GTP-bound active state. Little is known about primary or acquired resistance. Acquired resistance does occur and may be due to genetic alterations in the nucleotide exchange function or adaptative mechanisms in either downstream pathways or in newly expressed KRAS G12C mutation.
Highlights
Lung cancer remains the leading malignancy worldwide in terms of incidence and mortality
Despite the clinical benefit observed for many patients treated with KRAS G12C inhibitors, acquired resistance to single-agent therapy occurred in most patients [11,19,42,45,46]
Even most of the second-site resistance KRAS mutation occurred at residues involved in drug binding; several mutations associated with resistance to adagrasib and sotorasib were detected in amino-acids located outside the drug-binding pockets in including known oncogenic mutations at codons 13, 59, 61, 117, and 146 that impede GTP hydrolysis or promote GDP to GTP nucleotide exchange [47]
Summary
Lung cancer remains the leading malignancy worldwide in terms of incidence and mortality. New precision medicine is based on molecular characteristics of tumors with the detection of biomarkers of oncogenic drivers having predictive value. Such medicine is based on the existence of predictive molecular alterations, diagnostic assays, and effective targeted therapeutic agents. New molecular techniques applied for biomarker detection in lung tumors, such as mutations or gene fusions, favored the development of new effective drugs targeting other oncogenic drivers, such as ROS-1 fusions, BRAF mutation V600E, and other rare alterations such as MET delta 14 mutations, RET fusions, NTRK fusions. We report the biological basis and prevalence of KRAS mutations in lung cancer, the molecular techniques for identification of such mutations, the overview of actual therapeutic strategies, the primary and secondary resistance to targeted KRAS agents, and the perspective of KRAS inhibition
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