Mechanisms of resistance to KRASG12C inhibitors in KRASG12C-mutated non-small cell lung cancer

Abstract

The KRAS protein, a product of the KRAS gene (V-ki-ras2 Kirsten rat sarcoma viral oncogene homolog), functions as a small GTPase that alternates between an active GTP-bound state (KRAS(ON)) and an inactive GDP-bound state (KRAS(OFF)). The KRAS^G12C mutation results in the accumulation of KRASG12C(OFF), promoting cell cycle survival and proliferation primarily through the canonical MAPK and PI3K pathways. The KRAS^G12C mutation is found in 13% of lung adenocarcinomas. Previously considered undruggable, sotorasib and adagrasib are the first available OFF-state KRASG12C inhibitors, but treatment resistance is frequent. In this review, after briefly summarizing the KRAS pathway and the mechanism of action of OFF-state KRASG12C inhibitors, we discuss primary and acquired resistance mechanisms. Acquired resistance is the most frequent, with "on-target" mechanisms such as a new KRAS mutation preventing inhibitor binding; and "off-target" mechanisms leading to bypass of KRAS through gain-of-function mutations in other oncogenes such as NRAS, BRAF, and RET; or loss-of-function mutations in tumor suppressor genes such as PTEN. Other "off-target" mechanisms described include epithelial-to-mesenchymal transition and histological transformation. Multiple co-existing mechanisms can be found in patients, but few cases have been published. We highlight the lack of data on non-genomic resistance and the need for comprehensive clinical studies exploring histological, genomic, and non-genomic changes at resistance. This knowledge could help foster new treatment initiatives in this challenging context.

Keywords: KRASG12C inhibitor resistance; KRASG12C mutation; adagrasib; non-small cell lung cancer; sotorasib; translational research.

Figure 1

Model of KRASG12C-protein in the inactive GDP-bound state with important domains highlighted. 3D molecule was rendered with ProteinImager (http://3dproteinimaging.com) based on the crystal structure (PBD ID: 6OIM, rcsb.org/structure/6OIM). The structure of the KRAS gene comprises a G-domain coding region and a hypervariable region, including the conserved CAAX motif, a membrane anchor sequence (C: cysteine, A: aliphatic amino acids, X: any amino acid and residues coding for a lipid tail; not shown here). Selected structural regions of the KRAS protein G-domain are highlighted: the phosphate-binding loop (P-loop, amino acids (aa) 10 to 16) and the two switch regions (switch I (aa 30 to 38) and switch II (aa 59 to 67)). Both switch regions change conformation to make hydrogen bonds with the gamma-phosphate in GTP-bound-KRAS. Sotorasib is observed in its binding pocket (P2, behind Switch II region, near mutated Cysteine-12). The mutated Cystein-12 residue is shown in yellow. Adagrasib interacts with the P2 binding pocket in the same way as sotorasib.

Figure 2

Summary of "on-target" and "off-target" resistance mechanisms to OFF-state KRASG12C inhibitors. Summary of "on-target" and "off-target" resistance mechanisms described with OFF-state KRASG12C inhibitors sotorasib and adagrasib. "On-target" resistance encompasses new KRAS activating mutations and increased KRASG12C output due to growth factor receptors' feedback reactivation. "Off-target" resistance mechanisms include amplification or mutations of other oncogenes, upstream reactivation of wild-type KRAS and other RAS isoforms, epithelial-to-mesenchymal transition, and adeno-to-squamous transition. The illustration was created with BioRender.com. KRASG12Ci, OFF state KRASG12C inhibitor; GFR, Growth Factor Receptor.