Synergy of WEE1 and mTOR Inhibition in Mutant KRAS -Driven Lung Cancers

• Published in: Clinical cancer research Vol. 23; no. 22; pp. 6993 - 7005
• Main Authors: Hai, Josephine, Liu, Shengwu, Bufe, Lauren, Do, Khanh, Chen, Ting, Wang, Xiaoen, Ng, Christine, Li, Shuai, Tsao, Ming-Sound, Shapiro, Geoffrey I, Wong, Kwok-Kin
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 15-11-2017
• Subjects: Adenocarcinoma; Animal models; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - genetics; Biotechnology; Cancer; Caspases - metabolism; CDC2 Protein Kinase - metabolism; Cell Cycle Proteins - antagonists & inhibitors; Cell Line, Tumor; Cell Proliferation - drug effects; Cyclin D1; Cytotoxicity; Deoxyribonucleic acid; Disease Models, Animal; DNA; DNA damage; DNA Repair; Experimental design; Humans; Inhibition; K-Ras protein; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lungs; Mice; Models, Biological; Mutation; Non-small cell lung carcinoma; Nuclear Proteins - antagonists & inhibitors; Pharmacodynamics; Pharmacology; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; ras Proteins - genetics; Repair; Synergistic effect; Therapy; TOR protein; TOR Serine-Threonine Kinases - antagonists & inhibitors; Tumor cell lines; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-17-1098

-activating mutations are the most common oncogenic driver in non-small cell lung cancer (NSCLC), but efforts to directly target mutant KRAS have proved a formidable challenge. Therefore, multitargeted therapy may offer a plausible strategy to effectively treat
-driven NSCLCs. Here, we evaluate the efficacy and mechanistic rationale for combining mTOR and WEE1 inhibition as a potential therapy for lung cancers harboring
mutations.
We investigated the synergistic effect of combining mTOR and WEE1 inhibitors on cell viability, apoptosis, and DNA damage repair response using a panel of human
mutant and wild type NSCLC cell lines and patient-derived xenograft cell lines. Murine autochthonous and human transplant models were used to test the therapeutic efficacy and pharmacodynamic effects of dual treatment.
We demonstrate that combined inhibition of mTOR and WEE1 induced potent synergistic cytotoxic effects selectively in
-mutant NSCLC cell lines, delayed human tumor xenograft growth and caused tumor regression in a murine lung adenocarcinoma model. Mechanistically, we show that inhibition of mTOR potentiates WEE1 inhibition by abrogating compensatory activation of DNA repair, exacerbating DNA damage in
-mutant NSCLC, and that this effect is due in part to reduction in cyclin D1.
These findings demonstrate that compromised DNA repair underlies the observed potent synergy of WEE1 and mTOR inhibition and support clinical evaluation of this dual therapy for patients with
-mutant lung cancers.
.