KRASG12C抑制剂，如sotorasib和adagrasib，已经彻底改变了KRASG12C突变肿瘤患者的癌症治疗。然而，接受这些药物作为单药治疗的患者往往会出现药物抵抗。为了解决这个问题，我们评估了PAK4抑制剂KPT9274和KRASG12C抑制剂在胰腺导管腺癌（PDAC）和非小细胞肺癌（NSCLC）的体外模型中的组合应用。PAK4是一个重要的分子枢纽，连接了几个主要的信号通路，以及其在突变Ras驱动的癌症中的肿瘤形成作用。我们发现，对KRASG12C抑制剂产生耐药性的癌细胞对KPT9274导致的生长抑制敏感。此外，KPT9274与sotorasib和adagrasib协同抑制KRASG12C突变癌细胞的生长并减少其克隆形成潜力。机制上，这种组合抑制了细胞生长信号和下调了细胞周期标志物。在一个PDAC细胞系来源的异种移植瘤（CDX）模型中，KPT9274与sotorasib的亚优剂量组合显著减少了肿瘤负担（P = 0.002）。同样，对于一个NSCLC CDX模型，给予KPT9274作为维持治疗，在sotorasib停药后预防了肿瘤复发（P = 0.0001）。此外，KPT9274和sotorasib的组合增强了存活率。总之，本研究首次证明了KRASG12C抑制剂可以与PAK4抑制剂KPT9274协同作用，将KRASG12C抑制剂与KPT9274联合使用可以显著增强抗肿瘤活性和存活益处，为对KRASG12C抑制剂治疗不响应或产生耐药性的癌症患者提供了一种新的联合治疗方案。

KRASG12C inhibitors, such as sotorasib and adagrasib, have revolutionized cancer treatment for patients with KRASG12C 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 KRASG12C 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 KRASG12C inhibitor were sensitive to KPT9274 induced growth inhibition. Furthermore, KPT9274 synergized with sotorasib and adagrasib to inhibit the growth of KRASG12C 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 sub-optimal 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 KRASG12C inhibitors can synergize with the PAK4 inhibitor KPT9274 and combining KRASG12C inhibitors with KPT9274 can lead to remarkably enhanced antitumor activity and survival benefits, providing a novel combination therapy for cancer patients who do not respond or develop resistance to KRASG12C inhibitor treatment.