Fig. 1

KRAS^G12C signaling, mechanisms of resistance, and strategies of combating resistance: (1) Inhibitor bound KRAS^G12C-GDP is unable to be affected by GEF and can’t enter the activated GTP-bound state, however, upstream upregulation of RTKs and KRAS production can overcome the inhibition by stimulating GEF to act on the newly produced KRAS and inhibiting the function of GAP allowing for a constitutively on KRAS^G12C-GTP to drive cell growth down the MAPK pathway. (2) Mutation or amplification of other RAS isoforms can feed into the MAPK pathway and drive inhibitor resistant growth. (3) Direct inhibition of GTP bound KRAS^G12C to target upstream or KRAS mediated resistance. (4) Upstream inhibition of RTKs (EGFR/HER, FGFR2, MET, RET, etc.), SHP2, or SOS1 can target the mutated/upregulated upstream bypass mechanisms. (5) Downstream MAPK pathway inhibition using AURKA, RAF, MEK, and ERK inhibitors can be used to target multiple mechanisms of resistance including (1) and (2). (6) KRAS^G12C promotes a pro-inflammatory tumor microenvironment which diminishes lasting anti-tumor functionality. Cytotoxic chemotherapeutic agents, cell checkpoint inhibitors, or PD-1/L1 inhibitors can help promote tumor cell death. (7) The PI3K/AKT/mTOR pathway is activated in parallel during KRAS^G12C inhibition and can be targeted with (4) or via pathway specific PI3K, AKT, or mTOR inhibitors. _{Created with BioRender.com}