KRAS in NSCLC: State of the Art and Future Perspectives

Abstract

In NSCLC, KRAS mutations occur in up to 30% of all cases, most frequently at codon 12 and 13. KRAS mutations have been linked to adenocarcinoma histology, positive smoking history, and Caucasian ethnicity, although differences have been described across KRAS mutational variants subtypes. KRAS mutations often concur with other molecular alterations, notably TP53, STK11, and KEAP1, which could play an important role in treatment efficacy and patient outcomes. For many years, KRAS mutations have been considered undruggable mainly due to a high toxicity profile and low specificity of compounds. Sotorasib and adagrasib are novel KRAS inhibitors that recently gained FDA approval for pre-treated KRAS mutant NSCLC patients, and other molecules such as GDC-6036 are currently being investigated with promising results. Despite their approval, the efficacy of these drugs is lower than expected and progression among responders has been reported. Mechanisms of acquired resistance to anti-KRAS molecules typically involves either on target secondary mutations (e.g., G12, G13, Q61H, R68S, H95, Y96C, V8L) or off-target alterations. Ongoing trials are currently evaluating strategies for implementing efficacy and overcoming acquired resistance to these compounds. Finally, the efficacy of immune-checkpoint inhibitors still needs to be completely assessed and responses to anti-PD-1/PD-L1 agents may strongly depend on concomitant mutations.

Keywords: AMG 510; KRAS; MRTX849; NSCLC; acquired resistance; adagrasib; immune-checkpoint inhibitors; lung cancer; sotorasib.

Figure 1

KRAS activation and its downstream pathway. KRAS proteins are key elements in transducing extracellular signaling to downstream pathways. Intracellular KRAS proteins may present in two functional forms, KRAS-GTP and KRAS-GDP, which correspond to their active and inactive state, respectively. Transition from the KRAS-GDP to KRAS-GTP binding state is usually mediated by GEFs proteins and occurs via other adaptor and recruiter proteins, such as Grb2 and SHP-2. Conversely, transition from KRAS-GDP to KRAS-GTP usually requires GAPs proteins. Downstream signaling of KRAS normally includes RAF-MEK-ERK, PI3K/AKT and RAL pathways, implied in the regulation of cellular proliferation, migration, and death.

Figure 2

Mechanism of action of novel KRAS inhibitors. KRAS G12C mutants still depend on their GTP binding state in order to be fully active. By covalently binding the switch pocket II, sotorasib and adagrasib reduce KRAS G12C-GDP availability, thus impairing transition to the KRAS-GTP active form.

Figure 3

Molecular structure of sotorasib and adagrasib. KRAS G12C inhibitors sotorasib and adagrasib have been recently approved for a similar setting. However, differences in their molecular structure are here presented.