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Beglyarova N , Banina E , Zhou Y , Mukhamadeeva R , Andrianov G , Bobrov E , Lysenko E , Skobeleva N , Gabitova L , Restifo D , Pressman M , Serebriiskii IG , Hoffman JP , Paz K , Behrens D , Khazak V , Jablonski SA , Weiner LM , Golemis EA , Astsaturov I
Screening of conditionally reprogrammed patient-derived carcinoma cells identifies ERCC3-MYC interactions as a target in pancreatic cancer
Clin Cancer Res. 2016 Dec 15;22(24) :6153-6163
PMID: 27384421    PMCID: PMC5161635    URL: http://www.ncbi.nlm.nih.gov/pubmed/27384421
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PURPOSE: Even when diagnosed prior to metastasis, pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with almost 90% lethality, emphasizing the need for new therapies optimally targeting the tumors of individual patients. EXPERIMENTAL DESIGN: We first developed a panel of new physiological models for study of PDAC, expanding surgical PDAC tumor samples in culture using short-term culture and conditional reprogramming with the Rho kinase inhibitor Y-27632, and creating matched patient-derived xenografts (PDX). These were evaluated for sensitivity to a large panel of clinical agents, and promising leads further evaluated mechanistically. RESULTS: Only a small minority of tested agents was cytotoxic in minimally passaged PDAC cultures in vitro. Drugs interfering with protein turnover and transcription were among most cytotoxic. Among transcriptional repressors, triptolide, a covalent inhibitor of ERCC3, was most consistently effective in vitro and in vivo causing prolonged complete regression in multiple PDX models resistant to standard PDAC therapies. Importantly, triptolide showed superior activity in MYC-amplified PDX models, and elicited rapid and profound depletion of the oncoprotein MYC, a transcriptional regulator. Expression of ERCC3 and MYC was interdependent in PDACs, and acquired resistance to triptolide depended on elevated ERCC3 and MYC expression. TCGA analysis indicates ERCC3 expression predicts poor prognosis, particularly in CDKN2A-null, highly proliferative tumors. CONCLUSIONS: This provides initial preclinical evidence for an essential role of MYC-ERCC3 interactions in PDAC, and suggests a new mechanistic approach for disruption of critical survival signaling in MYC-dependent cancers.
Beglyarova, Natalya Banina, Eugenia Zhou, Yan Mukhamadeeva, Ramilia Andrianov, Grigorii Bobrov, Egor Lysenko, Elena Skobeleva, Natalya Gabitova, Linara Restifo, Diana Pressman, Max Serebriiskii, Ilya G Hoffman, John P Paz, Keren Behrens, Diana Khazak, Vladimir Jablonski, Sandra A Weiner, Louis M Golemis, Erica A Astsaturov, Igor K22 CA160725/CA/NCI NIH HHS/United States P30 CA006927/CA/NCI NIH HHS/United States P30 CA051008/CA/NCI NIH HHS/United States R01 CA188430/CA/NCI NIH HHS/United States R21 CA164205/CA/NCI NIH HHS/United States Clin Cancer Res. 2016 Jul 6. pii: clincanres.0149.2016.