Direct Targeting KRAS Mutation in Non-Small Cell Lung Cancer: Focus on Resistance

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.

Daily Practice Assessment of KRAS Status in NSCLC Patients: A New Challenge for the Thoracic Pathologist Is Right around the Corner

“…More than 50% of the patients treated with sotorasib and adagrasib do not show significant tumor reduction when treated with these specific KRAS G12C inhibitors [ 140 , 141 , 142 , 143 ]. Moreover, resistance to these molecules occurred relatively early, most of the time a few months following the treatment initiation [ 139 ].…”

“…Therefore, recent clinical data showed that the duration of response for the great majority after sotorasib treatment is quite short, since the median progression-free survival is around 6 months [ 23 ]. These different results stress the urgent need to better characterize the resistance pathways that can be induced by the KRAS G12C inhibitors [ 139 , 142 ]. In fact, different mechanisms of primary and secondary resistances occurring in KRAS -mutated NSCLC patients treated with these inhibitors can explain these clinical results ( Figure 2 ) [ 141 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 ].…”

Pragmatic Expectancy on Microbiota and Non-Small Cell Lung Cancer: A Narrative Review

“…Therefore, it should be hypothesized that the KRAS-activated signal might lead to the avoidance of the growth-inhibitory effects of butyrate. Although no direct experimental reports evaluate the role of SCFA in the lung epithelium, the observations made on the gut should be of potential interest also in the NSCLC context, since KRAS genetic changes are frequently detected in those tumors aroused in smoker subjects and might be kept under consideration in treatment design and approach [58][59][60]. Smoke affects bacteria in different ways [61].…”

Application of Compositions Comprising a KRAS G12C Inhibitor and an EGFR Inhibitor for the Potential Treatment of Cancer

“…The table below shows the anti-tumor activity of Compound 1 compared to that of a single agent (erlotinib or cetuximab) dosed alone or in combination in nude mice with human NCI-H2122 NSCLC xenograft tumors, where Cl = confidence interval and TGI = tumor growth inhibition. …”