Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma.

Autor:	Saha SK; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Gordan JD; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California., Kleinstiver BP; Molecular Pathology Unit, Center for Cancer Research, and Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, Massachusetts. Department of Pathology, Harvard Medical School, Boston, Massachusetts., Vu P; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Najem MS; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Yeo JC; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Shi L; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Kato Y; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Levin RS; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California., Webber JT; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California., Damon LJ; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Egan RK; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Greninger P; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., McDermott U; Wellcome Trust Sanger Institute, Hinxton, UK., Garnett MJ; Wellcome Trust Sanger Institute, Hinxton, UK., Jenkins RL; Department of Transplantation, Lahey Hospital and Medical Center, Burlington, Massachusetts., Rieger-Christ KM; Department of Translational Research, Lahey Hospital and Medical Center, Burlington, Massachusetts., Sullivan TB; Department of Translational Research, Lahey Hospital and Medical Center, Burlington, Massachusetts., Hezel AF; University of Rochester School of Medicine, Rochester, New York., Liss AS; Department of Surgery and the Andrew L. Warshaw, MD, Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts., Mizukami Y; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. Center for Clinical and Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo, Hokkaido, Japan., Goyal L; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Ferrone CR; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Zhu AX; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Joung JK; Molecular Pathology Unit, Center for Cancer Research, and Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, Massachusetts. Department of Pathology, Harvard Medical School, Boston, Massachusetts., Shokat KM; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California. Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California., Benes CH; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. nelbardeesy@partners.org cbenes@mgh.harvard.edu., Bardeesy N; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. nelbardeesy@partners.org cbenes@mgh.harvard.edu.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2016 Jul; Vol. 6 (7), pp. 727-39. Date of Electronic Publication: 2016 May 26.
DOI:	10.1158/2159-8290.CD-15-1442
Abstrakt:	Unlabelled: Intrahepatic cholangiocarcinoma (ICC) is an aggressive liver bile duct malignancy exhibiting frequent isocitrate dehydrogenase (IDH1/IDH2) mutations. Through a high-throughput drug screen of a large panel of cancer cell lines, including 17 biliary tract cancers, we found that IDH mutant (IDHm) ICC cells demonstrate a striking response to the multikinase inhibitor dasatinib, with the highest sensitivity among 682 solid tumor cell lines. Using unbiased proteomics to capture the activated kinome and CRISPR/Cas9-based genome editing to introduce dasatinib-resistant "gatekeeper" mutant kinases, we identified SRC as a critical dasatinib target in IDHm ICC. Importantly, dasatinib-treated IDHm xenografts exhibited pronounced apoptosis and tumor regression. Our results show that IDHm ICC cells have a unique dependency on SRC and suggest that dasatinib may have therapeutic benefit against IDHm ICC. Moreover, these proteomic and genome-editing strategies provide a systematic and broadly applicable approach to define targets of kinase inhibitors underlying drug responsiveness. Significance: IDH mutations define a distinct subtype of ICC, a malignancy that is largely refractory to current therapies. Our work demonstrates that IDHm ICC cells are hypersensitive to dasatinib and critically dependent on SRC activity for survival and proliferation, pointing to new therapeutic strategies against these cancers. Cancer Discov; 6(7); 727-39. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 681. (©2016 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu