KRASG12C inhibitors have revolutionized the treatment landscape for cancer patients harboring the G12C mutant isoform of KRAS. With the recent FDA approval of sotorasib and adagrasib, patients now have access to more promising treatment options. However, patients who receive these agents as a monotherapy usually develop drug resistance. Thus, there is a need to develop logical combination strategies that can delay or prevent the onset of resistance and simultaneously enhance the antitumor effectiveness of the treatment regimen. In this study, we aimed at pharmacologically targeting PAK4 by KPT9274 in combination with KRASG12C inhibitors in KRASG12C mutant pancreatic ductal adenocarcinoma (PDAC) and nonâ€"small cell lung cancer (NSCLC) preclinical models. PAK4 is a hub molecule that links several major signaling pathways and is known for its tumorigenic role in mutant Ras-driven cancers. We assessed the cytotoxicity of PAK4 and KRASG12C inhibitors combination in KRASG12C mutant 2D and 3D cellular models. KPT9274 synergized with both sotorasib and adagrasib in inhibiting the growth of KRASG12C mutant cancer cells. The combination was able to reduce the clonogenic potential of KRASG12C mutant PDAC cells. We also evaluated the antitumor activity of the combination in a KRASG12C mutant PDAC cell line-derived xenograft (CDX) model. Oral administration of a sub-optimal dose of KPT9274 in combination with sotorasib (at one-fourth of MTD) demonstrated significant inhibition of the tumor burden ( p = 0.002). Similarly, potent antitumor efficacy was observed in an NSCLC CDX model where KPT9274, acting as an adjuvant, prevented tumor relapse following the discontinuation of sotorasib treatment ( p = 0.0001). KPT9274 and sotorasib combination also resulted in enhanced survival. This is the first study showing that KRASG12C inhibitors can synergize with PAK4 inhibitor KPT9274 both in vitro and in vivo resulting in remarkably enhanced antitumor activity and survival outcomes.KRASG12C inhibitors demonstrate limited durable response in patients with KRASG12C mutations. In this study, combining PAK4 inhibitor KPT9274 with KRASG12C inhibitors has resulted in potent antitumor effects in preclinical cancer models of PDAC and NSCLC. Our results bring forward a novel combination therapy for cancer patients that do not respond or develop resistance to KRASG12C inhibitor treatment.

Anticancer efficacy of KRASG12C inhibitors is potentiated by PAK4 inhibitor KPT9274 in preclinical models of KRASG12C mutant pancreatic and lung cancers