Gemcitabine and Chk1 Inhibitor AZD7762 Synergistically Suppress the Growth of Lkb1-Deficient Lung Adenocarcinoma

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 18; pp. 5068 - 5076
• Main Authors: Liu, Yan, Li, Yuyang, Wang, Xiaoen, Liu, Feiyang, Gao, Peng, Quinn, Max M, Li, Fei, Merlino, Ashley A, Benes, Cyril, Liu, Qingsong, Gray, Nathanael S, Wong, Kwok-Kin
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research, Inc 15.09.2017
• Subjects: Adenocarcinoma; Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Animal models; Animals; Antimetabolites, Antineoplastic - pharmacology; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Proliferation; Checkpoint Kinase 1 - antagonists & inhibitors; CHK1 protein; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; DNA damage; Drug Synergism; Drug Therapy, Combination; Female; Gemcitabine; Genetic engineering; Humans; K-Ras protein; LKB1 protein; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Metabolism; Mice; Mice, Knockout; Mice, Nude; Monoclonal antibodies; p53 Protein; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins p21(ras) - genetics; Targeted cancer therapy; Thiophenes - pharmacology; Tumor Cells, Cultured; Tumor suppressor genes; Tumor Suppressor Protein p53 - physiology; Tumors; Urea - analogs & derivatives; Urea - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-17-0567

Cells lacking the tumor suppressor gene alter their metabolism to match the demands of accelerated growth, leaving them highly vulnerable to stress. However, targeted therapy for LKB1-deficient cancers has yet to be reported. In both cell lines and a genetically engineered mouse model of -induced lung cancer, much higher rates of DNA damage occur, resulting in increased dependence on Chk1 checkpoint function. Here we demonstrate that short-term treatment with the Chk1 inhibitor AZD7762 reduces metabolism in pembrolizumab tumors, synergizing with the DNA-damaging drug gemcitabine to reduce tumor size in these models. Our results offer preclinical proof of concept for use of a Chk1 inhibitor to safely enhance the efficacy of gemcitabine, particularly in aggressive KRAS-driven LKB1-deficient lung adenocarcinomas. .