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  • 1
    Abstract: Small cell lung cancer (SCLC) patient-derived xenografts (PDX) can be generated from biopsies or circulating tumor cells (CTC), though scarcity of tissue and low efficiency of tumor growth have previously limited these approaches. Applying an established clinical-translational pipeline for tissue collection and an automated microfluidic platform for CTC enrichment, we generated 17 biopsy-derived PDXs and 17 CTC-derived PDXs in a 2-year timeframe, at 89% and 38% efficiency, respectively. Whole-exome sequencing showed that somatic alterations are stably maintained between patient tumors and PDXs. Early-passage PDXs maintain the genomic and transcriptional profiles of the founder PDX. In vivo treatment with etoposide and platinum (EP) in 30 PDX models demonstrated greater sensitivity in PDXs from EP-naive patients, and resistance to EP corresponded to increased expression of a MYC gene signature. Finally, serial CTC-derived PDXs generated from an individual patient at multiple time points accurately recapitulated the evolving drug sensitivities of that patient's disease. Collectively, this work highlights the translational potential of this strategy.Significance: Effective translational research utilizing SCLC PDX models requires both efficient generation of models from patients and fidelity of those models in representing patient tumor characteristics. We present approaches for efficient generation of PDXs from both biopsies and CTCs, and demonstrate that these models capture the mutational landscape and functional features of the donor tumors. Cancer Discov; 8(5); 600-15. (c)2018 AACR.This article is highlighted in the In This Issue feature, p. 517.
    Type of Publication: Journal article published
    PubMed ID: 29483136
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  • 2
    Publication Date: 2018-01-04
    Description: Purpose: Epithelial-to-mesenchymal transition (EMT) confers resistance to a number of targeted therapies and chemotherapies. However, it has been unclear why EMT promotes resistance, thereby impairing progress to overcome it. Experimental Design: We have developed several models of EMT-mediated resistance to EGFR inhibitors (EGFRi) in EGFR -mutant lung cancers to evaluate a novel mechanism of EMT-mediated resistance. Results: We observed that mesenchymal EGFR -mutant lung cancers are resistant to EGFRi-induced apoptosis via insufficient expression of BIM, preventing cell death despite potent suppression of oncogenic signaling following EGFRi treatment. Mechanistically, we observed that the EMT transcription factor ZEB1 inhibits BIM expression by binding directly to the BIM promoter and repressing transcription. Derepression of BIM expression by depletion of ZEB1 or treatment with the BH3 mimetic ABT-263 to enhance "free" cellular BIM levels both led to resensitization of mesenchymal EGFR -mutant cancers to EGFRi. This relationship between EMT and loss of BIM is not restricted to EGFR -mutant lung cancers, as it was also observed in KRAS -mutant lung cancers and large datasets, including different cancer subtypes. Conclusions: Altogether, these data reveal a novel mechanistic link between EMT and resistance to lung cancer targeted therapies. Clin Cancer Res; 24(1); 197–208. ©2017 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 3
    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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