Publication Date:
2014-11-15
Description:
Targeted cancer therapies have produced substantial clinical responses, but most tumors develop resistance to these drugs. Here, we describe a pharmacogenomic platform that facilitates rapid discovery of drug combinations that can overcome resistance. We established cell culture models derived from biopsy samples of lung cancer patients whose disease had progressed while on treatment with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors and then subjected these cells to genetic analyses and a pharmacological screen. Multiple effective drug combinations were identified. For example, the combination of ALK and MAPK kinase (MEK) inhibitors was active in an ALK-positive resistant tumor that had developed a MAP2K1 activating mutation, and the combination of EGFR and fibroblast growth factor receptor (FGFR) inhibitors was active in an EGFR mutant resistant cancer with a mutation in FGFR3. Combined ALK and SRC (pp60c-src) inhibition was effective in several ALK-driven patient-derived models, a result not predicted by genetic analysis alone. With further refinements, this strategy could help direct therapeutic choices for individual patients.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388482/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388482/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Crystal, Adam S -- Shaw, Alice T -- Sequist, Lecia V -- Friboulet, Luc -- Niederst, Matthew J -- Lockerman, Elizabeth L -- Frias, Rosa L -- Gainor, Justin F -- Amzallag, Arnaud -- Greninger, Patricia -- Lee, Dana -- Kalsy, Anuj -- Gomez-Caraballo, Maria -- Elamine, Leila -- Howe, Emily -- Hur, Wooyoung -- Lifshits, Eugene -- Robinson, Hayley E -- Katayama, Ryohei -- Faber, Anthony C -- Awad, Mark M -- Ramaswamy, Sridhar -- Mino-Kenudson, Mari -- Iafrate, A John -- Benes, Cyril H -- Engelman, Jeffrey A -- 086357/Wellcome Trust/United Kingdom -- 102696/Wellcome Trust/United Kingdom -- 1U54HG006097-01/HG/NHGRI NIH HHS/ -- P50 CA090578/CA/NCI NIH HHS/ -- P50CA090578/CA/NCI NIH HHS/ -- R01 CA137008/CA/NCI NIH HHS/ -- R01 CA164273/CA/NCI NIH HHS/ -- R01CA137008/CA/NCI NIH HHS/ -- R01CA164273/CA/NCI NIH HHS/ -- U54 HG006097/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2014 Dec 19;346(6216):1480-6. doi: 10.1126/science.1254721. Epub 2014 Nov 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA. ; Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology and Harvard Medical School, Boston, MA 02115, USA. Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, 136-791, South Korea. ; Massachusetts General Hospital Cancer Center, Department of Pathology and Harvard Medical School, Boston, MA 02114, USA. ; Massachusetts General Hospital Cancer Center, Department of Medicine and Harvard Medical School, Boston, MA 02114, USA. jengelman@partners.org cbenes@partners.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25394791" target="_blank"〉PubMed〈/a〉
Keywords:
Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
;
Carcinoma, Non-Small-Cell Lung/*drug therapy/enzymology/genetics
;
DNA Mutational Analysis
;
Drug Resistance, Neoplasm/*genetics
;
Drug Screening Assays, Antitumor
;
Enzyme Activation/genetics
;
Humans
;
Lung Neoplasms/*drug therapy/enzymology/genetics
;
MAP Kinase Kinase 1/genetics/metabolism
;
Molecular Targeted Therapy/*methods
;
Mutation
;
*Patient-Specific Modeling
;
Protein Kinase Inhibitors/*therapeutic use
;
Proto-Oncogene Proteins pp60(c-src)/antagonists & inhibitors
;
Pyrimidines/therapeutic use
;
Receptor Protein-Tyrosine Kinases/antagonists & inhibitors
;
Receptor, Epidermal Growth Factor/antagonists & inhibitors
;
Receptor, Fibroblast Growth Factor, Type 3/antagonists & inhibitors/genetics
;
Sulfones/therapeutic use
;
Tumor Cells, Cultured
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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