Anticancer Efficacy of KRAS(G12C) Inhibitors Is Potentiated by PAK4 Inhibitor KPT9274 in Preclinical Models of KRAS(G12C)-Mutant Pancreatic and Lung Cancers

KRAS(G12C) inhibitors, such as sotorasib and adagrasib, have revolutionized cancer treatment for patients with KRAS(G12C)-mutant tumors. However, patients receiving these agents as monotherapy often develop drug resistance. To address this issue, we evaluated the combination of the PAK4 inhibitor KPT9274 and KRAS(G12C) inhibitors in preclinical models of pancreatic ductal adenocarcinoma (PDAC) and non–small cell lung cancer (NSCLC). PAK4 is a hub molecule that links several major signaling pathways and is known for its tumorigenic role in mutant Ras–driven cancers. We found that cancer cells resistant to KRAS(G12C) inhibitor were sensitive to KPT9274-induced growth inhibition. Furthermore, KPT9274 synergized with sotorasib and adagrasib to inhibit the growth of KRAS(G12C)-mutant cancer cells and reduce their clonogenic potential. Mechanistically, this combination suppressed cell growth signaling and downregulated cell-cycle markers. In a PDAC cell line–derived xenograft (CDX) model, the combination of a suboptimal dose of KPT9274 with sotorasib significantly reduced the tumor burden (P= 0.002). Similarly, potent antitumor efficacy was observed in an NSCLC CDX model, in which KPT9274, given as maintenance therapy, prevented tumor relapse following the discontinuation of sotorasib treatment (P= 0.0001). Moreover, the combination of KPT9274 and sotorasib enhances survival. In conclusion, this is the first study to demonstrate that KRAS(G12C) inhibitors can synergize with the PAK4 inhibitor KPT9274 and combining KRAS(G12C) inhibitors with KPT9274 can lead to remarkably enhanced antitumor activity and survival benefits, providing a novel combination therapy for patients with cancer who do not respond or develop resistance to KRAS(G12C) inhibitor treatment.