NovelCombination to Enhance the Antitumor Activity ofKRASG12C Targeted Drugs
Recommended Citation
Khan HY, Bannoura SF, Aboukameel A, Li Y, Al-Hallak M, Al Sbihi A, Kim S, Beydoun R, Mohammad RM, Landesman Y, Baloglu E, Senapedis W, Sukari A, Nagasaka M, Philip PA, El-Rayes B, Shields A, Azmi AS. NovelCombination to Enhance the Antitumor Activity ofKRASG12C Targeted Drugs. 2022; (7):865.
Document Type
Conference Proceeding
Publication Date
8-1-2022
Abstract
Background: KRASG12C inhibitors sotorasib and adagrasib have shown promising results in preclinical and clinical studies. However, patients receiving these agents asmonotherapy usually develop drug resistance over time. This necessitates devising rational combination approaches that can prevent or delay the onset of resistance while enhancing the antitumor efficacy of the regimen. KRASG12C inhibitors efficiently block the KRAS pathway but have limited impact on the parallel oncogenic signaling driven by PI3K/AKT, which is regulated by the Rho GTPases alongside their effectors, the P21-activated kinases (PAKs). PAK4, the main effector of Rho GTPase Cdc42, is known for its role in mutant Ras-dependent tumor metastasis. Methods: In this study, we targeted two parallel signaling pathways by combining KRASG12C inhibitors with the PAK4 inhibitor KPT-9274 in KRASG12C mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) in vitro and in vivo models. We assessed the cytotoxicity of the combination in KRASG12C mutant 2D and 3D cellular models. We also evaluated the anti-tumor activity of the combination in a KRASG12C mutant pancreatic cancer cell line-derived xenograft model. Results: KPT-9274 synergized with both sotorasib and adagrasib in inhibiting the growth ofKRASG12Cmutant cancer cells in 2D and 3Dcultures, but not in KRASwt, KRASG12Vand KRASG12D cell lines (NCI RASless MEFs). The combination also reduced the clonogenic potential ofKRASG12C mutant pancreatic cancer cells. Treatment with PAK4-KRASG12C inhibitor combination resulted in enhanced and prolonged inhibition of KRAS downstream effector pathways. Oral administration of KPT-9274 at a suboptimal dose (100 mg/kg QD × 5 × 3 weeks) and sotorasib at one-fourth of MTD (25 mg/kg QD × 5 × 3 weeks) demonstrated remarkable inhibition of the tumor burden. Conclusions: This is the first study showing that KRASG12C inhibitors can synergize with PAK4 inhibitors resulting in improved antitumor activity.
Issue
7
First Page
865
