Abstract A77: Screening of conditionally reprogrammed patient-derived carcinoma cells identifies ERCC3-MYC interactions as a target in pancreatic cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2016-12, Vol.76 (24_Supplement), p.A77-A77
• Main Authors: Astsaturov, Igor, Jablonski, Sandra A., Zhou, Yan, Serebriiskii, Ilya, Keren, Paz, Weiner, Louis M., Golemis, Erica, Khazak, Vladimir
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.PANCA16-A77

Methods: Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy that affects 44,000 individuals yearly in the US. The list of agents active against PDAC is limited. We explored in an unbiased fashion the clinically available drugs to identify novel cytotoxics using new physiological models for PDAC including cells rapidly expanded in vitro from surgical or xenografted tumors (PDX). Results: Not unexpectedly, only a small minority of agents showed activity against pancreatic carcinoma cells in vitro. Among these, transcriptional repressors and drugs interfering with protein folding and biosynthesis ranked as most cytotoxic. Triptolide, a covalent inhibitor of the ERCC3, a bifunctional regulator of transcription and DNA repair, was most consistently effective in vitro and highly effective in vivo, causing prolonged complete regression in multiple PDX models. Importantly, triptolide showed superior activity in MYC-amplified PDX models, suggesting a critical role for ERCC3 in this subset. Triptolide elicited rapid and profound depletion of MYC oncoprotein, a transcriptional co-factor for ERCC3. Expression of ERCC3 was MYC-dependent, while resistance to triptolide was associated with elevated ERCC3 and MYC expression. Furthermore, high ERCC3 mRNA level was associated with decreased survival of PDAC patients. Conclusions: These findings provide preclinical evidences for transcriptional vulnerability in PDAC via ERCC3 targeting and a new mechanistic approach for disruption of MYC-dependent pancreatic cancers. Citation Format: Igor Astsaturov, Sandra A. Jablonski, Yan Zhou, Ilya Serebriiskii, Paz Keren, Louis M. Weiner, Erica Golemis, Vladimir Khazak.{Authors}. Screening of conditionally reprogrammed patient-derived carcinoma cells identifies ERCC3-MYC interactions as a target in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A77.