Abstract:
:Cells lacking the tumor suppressor gene LKB1/STK11 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 Kras/p53/Lkb1 cell lines and a genetically engineered mouse model of Kras/p53/Lkb1-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. Cancer Res; 77(18); 5068-76. ©2017 AACR.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Liu Y,Li Y,Wang X,Liu F,Gao P,Quinn MM,Li F,Merlino AA,Benes C,Liu Q,Gray NS,Wong KKdoi
10.1158/0008-5472.CAN-17-0567subject
Has Abstractpub_date
2017-09-15 00:00:00pages
5068-5076issue
18eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-17-0567journal_volume
77pub_type
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