HuR regulates Poly ADP Ribose Glycohydrolase: Implications for PARP inhibitor efficacy in pancreatic ductal adenocarcinoma cells

Saswati Chand, Thomas Jefferson University

Abstract

Overcoming drug resistance requires identification of redundant survival signals. Even in the best case scenario of personalized medicine wherein cancer- specific genomic alterations are treated with molecular targeted therapeutics, increasing resistance predicates concurrent identification of compensatory mechanisms. For a lethal malignancy with limited treatment options such as pancreatic ductal adenocarcinoma ( PDA), the development and clinical implementation of a novel targeted strategy i.e. PARP inhibitors was a major breakthrough. However, PARPi have not progressed as a frontline therapy for PDA patients despite being in the clinical trials pipeline for over a decade now. Identifying and combating de novo and acquired PARPi resistance mechanisms is a critical medical goal in oncology, and the focus of this study. Attempts to target the most frequent mutations in PDA patient samples, including KRAS (86%), TP53 (68%), CDKN2A (21%), SMAD4 (21%) and EGFR (7%) identified through multiple next-generation sequencing studies haven’t yielded any considerable success. However, over 10% of PDA patients are associated with germline or sporadic loss of DNA repair and genome maintenance genes, specifically BRCA1 and BRCA2, which compromises repair of damaged DNA resulting in increased chromosomal instability (CIN). Paradoxically, while CIN promotes tumorigenesis, these genetic mutations become the tumor cells’ “Achilles heel”. These DDR- defective cells rely heavily on an alternative DNA repair pathway dictated by PARP1, and thus are particularly susceptible to PARP inhibitors and intra-strand crosslinkers such as mitomycin C, cisplatin, etc. Therefore, DNA damage repair (DDR), one of twelve core signaling pathways dysregulated in PDA, has provided a promising approach for treating selective patients with DNA repair-deficient tumors. Unfortunately, there is an unmet demand to understand how initially responsive patients develop resistance to PARPi. While genomic and proteomic alterations, such as BRCA reversion mutation or upregulation of a PARPi efflux pump respectively, have been widely explored as PARPi resistance mechanisms, rapid reprogramming of the RNA expression signature in response to PARPi exposure has been largely ignored. This is the first study to demonstrate that post-transcriptional gene regulation (PTGR) by an RNA- binding protein HuR upregulates expression of a novel resistance gene Poly-ADP Ribose Glycohydrolase (PARG) which supports DNA damage response and facilitates PARPi resistance. We have previously shown that HuR-mediated transcriptomic rewiring causes PDA cells to reprogram core cellular processes and enhance expression of several pro-survival factors such as DCK, WEE1 and PIM1 which, in turn, support acute chemoresistance and survival of PDA cells in a harsh tumor microenvironment. The ultimate clinical goal of this study relates to 1) optimizing and extending a proven synthetic lethal therapeutic strategy to all pancreatic cancer patients, regardless of their DNA-repair status, 2) recognizing PARG as a more suitable target over PARP1 due to its ability to be acutely induced in response to drug exposure and 3) inhibiting PARG and/or HuR as an effective therapeutic strategy to improve efficacy of not only PARP inhibitor therapy but other chemotherapy regimens in pancreatic cancer.

Subject Area

Molecular biology|Pharmacology|Biochemistry

Recommended Citation

Chand, Saswati, "HuR regulates Poly ADP Ribose Glycohydrolase: Implications for PARP inhibitor efficacy in pancreatic ductal adenocarcinoma cells" (2017). ETD Collection for Thomas Jefferson University. AAI10284920.
https://jdc.jefferson.edu/dissertations/AAI10284920

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