Abstract 4764: A global transcriptome analysis of pancreatic cancer cells distinguishes between acute and acquired PARP inhibitor resistance mechanisms
Authors: Aditi Jain, Matthew McCoy, Lebaron A. Agostini, Yuriy Gusev, Subha Madhavan, Michael Pishvaian, Sankar Addya, Eric Londin, Maria R. Gurevich, Chani Stossel, Talia Golan, Charles J. Yeo, Jonathan R. Brody
Journal: Cancer Research (2019)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer related deaths in the U.S. Recent advances in understanding RNA biology in PDAC have shed light on post-transcriptional regulation of genes and pathways through RNA binding proteins (RBP). Our lab has demonstrated that HuR, an RBP, is overexpressed in PDAC cells and stabilizes pro-survival mRNAs. Additionally, our work and others have demonstrated that this level of gene regulation can support drug resistance in PDAC cells. A synthetic lethal strategy employing Poly-ADP ribose polymerase inhibitors (PARPi) in a subset of patients with DNA repair deficient pancreatic cancers has been gaining interest. However, the success of PARPi is often hindered by the emergence of drug resistance in patients who initially respond. We have published that short-term PARPi treatment of PDAC cells causes activation of HuR where it stabilizes a DNA repair enzyme, PAR-glycohydrolase, and mediates acute PARPi resistance. In this study, we generated olaparib acquired resistant pancreatic cancer cells in vitro and acquired pancreatic patient derived xenograft cell lines (pre- and post PARPi) to understand acute versus acquired resistant mechanism(s). In characterising the acquired resistant model of PARPi resistance, we found that these cells are &amp;gt;20 fold more resistant to olaparib and platinums and &amp;gt;5 fold resistant to other PARPi like rucaparib and veliparib, compared to parental cells. No cross resistance was seen with other chemotherapeutics like gemcitabine. Additionally, we also found acquired resistant cells lost PARP-1 protein expression compared to parental cells. Bioinformatic analyses on HuR-RNA immunoprecipitation-microarray (RIP-microarray) data from acutely treated olaparib cells show enrichment of pro-survival mRNAs. Interestingly, these mRNAs are significantly downregulated in acquired resistant cells compared to control cells (i.e., negative log2 fold changes, p&amp;lt;0.001) in differential expression of HuR and HuR established targets. Interestingly, upregulated gene transcripts in these samples belong to pathways that negatively regulate biosynthetic and metabolic processes, and hence may represent pathways to target. Further, in vitro analyses show that parental PDAC cells are sensitive to combined inhibition of PARP and HuR but acquired resistant cells fail to respond to HuR inhibition. In conclusion, HuR mediates acute resistance to PARPi in PDAC cells and HuR inhibitor therapy could enhance PARPi therapy immediately, yet is most likely not useful in the setting of acquired- resistance. Future studies will explore genetic alterations and novel HuR-independent pathways in PARPi acquired resistant cells. Finally, we have begun a line of investigation of combining PARPi therapy with HuR inhibitors in an effort to optimize upfront therapeutic efficacy Citation Format: Aditi Jain, Matthew McCoy, Lebaron A. Agostini, Yuriy Gusev, Subha Madhavan, Michael Pishvaian, Sankar Addya, Eric Londin, Maria R. Gurevich, Chani Stossel, Talia Golan, Charles J. Yeo, Jonathan R. Brody. A global transcriptome analysis of pancreatic cancer cells distinguishes between acute and acquired PARP inhibitor resistance mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4764.