Fig. 6.

Mechanisms of adaptation or resistance to KRAS-G12C inhibitors. a. Production of new KRAS-G12C protein. Activation of the pathway involving epidermal growth factor receptor (EGFR)–SH2-containing protein tyrosine phosphatase 2 (SHP2)–SOS Ras/Rac guanine nucleotide exchange factor 1 (SOS1) is necessary to maintain the newly produced KRAS-G12C protein in an active GTP-bound form, which leads to the adaptation of ARS-1620 through the RAF-MEK-extracellular signal regulated kinase (ERK) pathway. The cell cycle regulator aurora kinase A (AURKA) can further enhance KRAS-G12C–mediated activation of mitogen-activated protein kinase (MAPK) effector pathways. b. Activating wild-type NRAS and HRAS. Multiple receptor tyrosine kinases (RTKs), rather than a single RTK, activate wild-type NRAS and HRAS, leading to acquired resistance to ARS-1620 and sotorasib by the RAF-MEK-ERK and the phosphatidylinositol 3-kinase (PI3K)-AKT-mechanistic target of rapamycin (mTOR) pathways. c. Inducing epithelial-to-mesenchymal transition (EMT). The insulin-like growth factor receptor (IGFR)-insulin receptor substrate 1 (IRS1) pathway mediates PI3K activation in a SHP2-independent manner, leading to acquired resistance to sotorasib or ARS-1620 through snail family transcriptional repressor 1 (SNAI1)-mediated EMT. d. Inducting secondary genetic alterations. An analysis of the genetic alterations of patients with acquired adagrasib resistance showed that 45% of the cases had a putative genetic mechanism of drug resistance. In short, acquired KRAS mutations in drug binding sites or oncogenic hotspots, gain-of-function mutations in the MAPK pathway, and loss-of-function mutations in tumor suppressor genes favor the acquisition of resistance to KRAS-G12C inhibitors