Targeting KRASG12C in colorectal cancer: the beginning of a new era

Abstract

RAS mutation is considered one of the most relevant oncogenic drivers in human cancers. Unfortunately, for more than three decades, RAS has been considered an undruggable target. Recently, the discovery of selective and potent KRAS^G12C inhibitors represented a light at the end of the tunnel. Indeed, sotorasib and adagrasib proved clinical activity in patients with refractory metastatic colorectal cancer harboring KRAS^G12C mutation; however, responses are lower than expected, suggesting the presence of intrinsic resistance. Consequently, novel combinatory strategies to disrupt the RAS signaling pathways are under clinical investigation. This review aims to discuss the current knowledge and novel routes of KRAS^G12C inhibition in metastatic colorectal cancer.

Keywords: CRC; KRAS(G12C); precision medicine; target therapies.

Figure 1

Ras signaling pathways. When ligands, such as epidermal growth factor (EGF), bind to the extracellular domain of a receptor tyrosine kinase (RTK), such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR), RTK dimerizes and activates a cascade of events. Son of sevenless (SOS), a guanine nucleotide exchange factor (GEF), is recruited via the adaptor proteins SH2-adaptor protein C (SHC) and growth factor receptor-bound protein 2 (Grb2). After exchanging guanosine diphosphate (GDP) with guanosine-5ʹ-triphosphate (GTP), Ras is activated and dimerizes. The mitogen-activated protein kinase (MAPK) pathway is activated after Ras binds Raf, thereby promoting its dimerization and activation, Mitogen-activated protein kinase 1 and 2 (MEK1/2) and extracellular regulated kinase 1/2 (ERK1/2) activation. Active GTP-bound Ras also binds to phosphatidylinositol 3-kinase (PI3K), leading to phosphorylation of the serine/threonine kinase Akt that further activates mammalian target of rapamycin (mTOR) complex, nuclear factor (NF)-kB and B-cell lymphoma-extra large (BCL)-X. Thirdly, activation of TIAM1 drives Rac, Rho and PAK activation. As a result, many downstream serum response factors (SRF) and other transcription factors determine oncogenic transcription, cell cycle progression, growth, survival, metabolism, apoptosis inhibition, cell motility and migration. RAS activation ends after a shift from GTP-bound to a GDP-bound state that is mediated by RAS–GTPase-activating enzymes (RAS–GAPs).