Anticancer Efficacy of KRASG12C Inhibitors Is Potentiated by PAK4 Inhibitor KPT9274 in Preclinical Models of KRASG12C-Mutant Pancreatic and Lung Cancers.

Autor:	Khan HY; Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan., Nagasaka M; University of California Irvine School of Medicine, Orange, California; Chao Family Comprehensive Cancer Center, Orange, California.; Division of Neurology, Department of Internal Medicine, St. Marianna University, Kawasaki, Japan., Aboukameel A; Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan., Alkhalili O; Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan., Uddin MH; Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan., Bannoura SF; Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan., Mzannar Y; Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan., Azar I; Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan., Beal EW; Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan., Tobon ME; Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan., Kim SH; Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan., Beydoun R; Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan., Baloglu E; Karyopharm Therapeutics, Newton, Massachusetts., Senapedis W; Karyopharm Therapeutics, Newton, Massachusetts., El-Rayes BF; University of Alabama, Birmingham, Alabama., Philip PA; Henry Ford Health, Detroit, Michigan.; Department of Pharmacology, Wayne State University, Detroit, Michigan., Mohammad RM; Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan., Shields AF; Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan., Al Hallak MN; Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan., Azmi AS; Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2023 Dec 01; Vol. 22 (12), pp. 1422-1433.
DOI:	10.1158/1535-7163.MCT-23-0251
Abstrakt:	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 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 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 patients with cancer who do not respond or develop resistance to KRASG12C inhibitor treatment. (©2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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