Table 3.

Overcoming Resistance to K-Ras^G12C Inhibition through Combinatorial Therapies

Combinatorial Strategy	Combination	Drug Combo	Reference	Mechanism of Action	Significance	Stage
RTK co-inhibition	K-RasG12C inhibitor + EGFR inhibitor	ARS-853 + Erlotinib ARS-853 + Gefitinib ARS-1620 + Erlotinib AMG-510 + Erlotinib	Patricelli et al.4 Lito et al.49 Ryan et al.11 Canon et al.6 Misale et al.12	targeting EGFR-mediated feedback resistance	highly effective in models that heavily depend on individual RTKs for feedback resistance, yet not universally effective across different KRASG12C mutant models	preclinical
	K-RasG12C inhibitor + HER kinases inhibitor	ARS-853 + Afatinib ARS-1620 + Afatinib AMG-510 + Afatinib MRTX849 + Afatinib	Patricelli et al.4 Lito et al.49 Ryan et al.11 Canon et al.6 Hallin et al.7	targeting HER kinases-mediated feedback resistance
	K-RasG12C inhibitor + c-MET inhibitor	ARS-853 + Crizotinib ARS-1620 + Crizotinib	Lito et al.49 Ryan et al.11	targeting c-MET-mediated feedback resistance
	K-RasG12C inhibitor + SRC/ABL inhibitor	ARS-853 + Saracatinib	Lito et al.49	targeting SRC/ABL-mediated feedback resistance
	K-RasG12C inhibitor + FGFR inhibitor	ARS-853 + PD173974 ARS-1620 + BGJ398	Lito et al.49 Ryan et al.11 Misale et al.12	targeting FGFR-mediated feedback resistance
SHP2 co-inhibition	K-RasG12C inhibitor + SHP2 inhibitor	ARS-1620 + SHP099 ARS-1620 + RMC-4550 AMG-510 + SHP099 AMG-510 + RMC-4550 MRTX849 + RMC-4550	Ryan et al.11 Xue et al.10 Canon et al.6 Hallin et al.7	overcoming K-RasG12C inhibition-mediated adaptive feedback resistance by co-targeting SHP2, which integrates signaling from multiple RTKs to Ras	a feasible strategy to improve the clinical efficacy of K-RasG12C inhibition across different models	phase 1 in preparation
SOS1 co-inhibition	K-RasG12C inhibitor + SOS1 inhibitor	ARS-853 + BAY-293	Hillig et al.79	blocking K-RasG12C reactivation by disrupting RAS-SOS1 interaction	first combinatorial strategy co-targeting the guanine nucleotide exchange reaction of Ras GTPase	preclinical
AURKA co-inhibition	K-RasG12C inhibitor + AURKA inhibitor	ARS-1620 + Alisertib	Xue et al.10	overcoming K-RasG12C reactivation and the escape of quiescence by disrupting Ras-Raf interaction	a proof-of-concept strategy co-targeting the reciprocal AURKA signaling pathway	preclinical
MAPK/ERK pathway co-inhibition	K-RasG12C inhibitor + MEK1/2 inhibitor	ARS-853 + Trametinib ARS-1620 + Trametinib AMG-510 + Trametinib	Patricelli et al.4 Lito et al.49 Misale et al.12 Canon et al.6	eliminating bypass or residual MEK1/2 signaling that induces resistance	effective in models that heavily depend on MAPK/ERK pathway for proliferation	preclinical
	K-RasG12C inhibitor + ERK inhibitor	ARS-853 + SCH984	Lito et al.49	inhibiting the feedback reactivation of ERK signaling	limited combinatorial effects
PI3K/AKT pathway co-inhibition	K-RasG12C inhibitor + PI3K inhibitor	ARS-853 + BAY806946 ARS-1620 + GDC0941 AMG-510 + AMG-511	Lito et al.49 Misale et al.12 Canon et al.6	overcoming resistance to K-RasG12C inhibition by either decreasing PIP3-bound-GABs that promote ERK reactivation, or inducing concomitant shut-down of both MAPK/ERK and PI3K/AKT pathways	highly effective in KRASG12C mutant models that take advantage of PI3K/AKT signaling for cell growth	preclinical
	K-RasG12C inhibitor + AKT inhibitor	ARS-853 + MK2206 ARS-1620 + MK2206 AMG-510 + AZD-5363	Lito et al.49 Misale et al.12 Canon et al.6	inducing concomitant shut-down of AKT/mTOR singling pathway, which promotes cell proliferation
	K-RasG12C inhibitor + mTOR inhibitor	ARS-853 + AZD8255 ARS-1620 + AZD8055 MRTX849 + Vistusertib	Lito et al.49 Misale et al.12 Hallin et al.7
RTK and mTOR co-inhibition	K-RasG12C inhibitor + IGF1R inhibitor + mTOR inhibitor	ARS-1620 + Linstinib + Everolimus	Molina-Arcas et al.15	co-targeting IGF1R and mTOR/AKT-mediated intrinsic and adaptive resistance	effective in KRAS mutant cells showing reduced KRAS dependency for growth	preclinical
Chemotherapy co-treatment	K-RasG12C inhibitor + chemotherapeutic	AMG-510 + Carboplatin	Canon et al.6	potentiating tumoricidal effects of K-RasG12C inhibitor by causing DNA damage	combining targeted K-RasG12C inhibition with a standard-of-care chemotherapeutic	preclinical
	K-RasG12C inhibitor + CDK4/6 inhibitor	MRTX849 + Palbociclib	Hallin et al.7	Blocking RB/E2F-dependent cell proliferation in CDKN2A-null models through K-RasG12C-CDK4/6 co-inhibition	effective in MRTX849-refractory models with CDKN2A homozygous deletion	preclinical
Immunotherapy co-treatment	K-RasG12C inhibitor + immune checkpoint inhibitor	AMG-510 + anti-PD-1 MRTX849 + anti-PD-1	Canon et al.6 Briere et al.13	potentiating K-RasG12C inhibition-driven antitumor immunity and immunological memory	unraveling a long-overlooked pairing between targeted therapy and immunotherapy in cancer treatment	phase 1 in preparation