Abstract 6183: A novel NQO1 bioactivatable drug induces mitochondrial dysfunction and G2/M phase cell cycle arrest to selectively kill pancreatic cancer cells

Aims: Pancreatic cancer is among the top five leading causes of cancer-related deaths worldwide, with poor overall survival rates. Current therapies for pancreatic cancer lack tumor specificity, resulting in harmful effects on normal tissues. Therefore, developing tumor-specific agents for the treatment of pancreatic cancer is critical. NAD(P)H:quinone oxidoreductase 1 (NQO1), highly expressed in pancreatic cancers but not in associated normal tissues, makes NQO1 bioactivatable drugs a potential therapy for selectively killing NQO1-positive cancer cells. Our previous studies have revealed that the novel NQO1 bioactivatable drug deoxynyboquinone (DNQ) is 10-fold more potent than the prototypic NQO1 bioactivatable drug β-lapachone in killing of NQO1-positive cancer cells. However, DNQ treatment results in high-grade methemoglobinemia, a significant side effect that limits clinical development. Results: Here, we report for the first time on a DNQ derivative, isopentyl-deoxynboquinone (IP-DNQ), which selectively kills pancreatic ductal adenocarcinoma (PDAC) cells in an NQO1-dependent manner with equal potency to the parent DNQ. IP-DNQ evokes massive reactive oxygen species (ROS) production and oxidative DNA lesions that result in poly(ADP-ribose)polymerase-1 (PARP1) hyperactivation, mitochondrial catastrophe, and G2/M phase cell cycle arrest, leading to apoptotic and necrotic programmed cell death. Importantly, IP-DNQ treatment causes only mild methemoglobinemia in vivo, with a threefold improvement in the maximum tolerated dose (MTD) compared with DNQ, while it significantly suppresses tumor growth and extends the life span of mice in subcutaneous and orthotopic pancreatic cancer xenograft models. Innovation and Conclusion: Our study demonstrates that IP-DNQ is a promising therapy for NQO1-positive pancreatic cancers and may enhance the efficacy of other anticancer drugs. IP-DNQ represents a novel approach to treating pancreatic cancer with the potential to improve patient outcomes.

Desmoplasia of Pancreatic Ductal Adenocarcinoma

Patients with pancreatic cancers have one of the highest mortality rates of any cancer with 5-year survival rates of 6%. The therapeutic responses of pancreatic cancers are highly variable and there is a desperate need for agents to specifically and efficaciously treat pancreatic cancer patients. We recently discovered that not only were NAD(P)H:quinone oxidoreductase 1 (NQO1) levels elevated 5- to 40-fold in >90% of pancreatic tumors vs associated normal tissue, but that catalase levels were inversely expressed comparatively, elevated in normal vs tumor tissue. NQO1 represents a unique target to exploit for the therapeutic elimination of pancreatic cancers. NQO1 bioactivatable drugs, such as β-lapachone (β-lap) or deoxynyboquinone (DNQ) and derivatives generate hydrogen peroxide as a mechanism to hyperactivate PARP1 and selectively kill tumors. In addition to catalase, reduced glutathione levels are essential for a cell's protection against hydrogen peroxide. Tumors with mutated KRAS, which constitutes >90% of pancreatic cancers, are metabolically reprogrammed to rely on glutamine to maintain the cell's NADPH and glutathione levels, and therefore, anti-oxidant state (Son et.al., Nature, 2013). The present study evaluated the therapeutic potential of inhibiting this KRAS-reprogrammed metabolic pathway with the small molecule GLS1 inhibitor, BPTES, in combination with NQO1-bioactivatable drugs, β-lapachone or IB-DNQ. Synergistic cell lethality was noted using non-lethal doses of BPTES combined with sublethal doses of β-lapachone in KRAS-driven pancreatic or non-small cell lung cancer cells. ROS levels in BPTES and β-lap treated cell lines were dramatically higher than the ROS levels with either agent alone. This was further supported by a dramatic loss of glutathione and NADPH following combination treatment vs either agent alone. Lethality was completely rescued by the addition of the NQO1 inhibitor, dicoumarol, demonstrating that synergy is dependent on the NQO1 activation of β-lap. Partial rescue was seen with the addition of cell permeable glutathione further demonstrating the importance of ROS in synergy. The addition of cell permeable malate and oxaloacetate, downstream metabolites of the KRAS-driven glutamine pathway, also rescued synergy. Our findings indicate that NQO1-bioactivatable drugs may improve the sensitivities of clinical grade GLS1 inhibitors in pancreatic cancer patients. Citation Format: Gaurab Chakrabarti, David A. Boothman. Inhibiting KRAS-reprogrammed glutamine metabolism sensitizes pancreatic cancer to NQO1-bioactivatable drugs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1679. doi:10.1158/1538-7445.AM2014-1679

The aminobisphosphonate zoledronic acid has elicited significant attention due to its remarkable anti-tumoral activity, although its detailed mechanism of action remains unclear. Here, we demonstrate the existence of a nuclear GSK-3β-NFATc2 stabilization pathway that promotes breast and pancreatic cancer growth in vitro and in vivo and serves as a bona fide target of zoledronic acid. Specifically, the serine/threonine kinase GSK-3β stabilizes nuclear NFATc2 through phosphorylation of the serine-rich SP2 domain, thus protecting the transcription factor from E3-ubiquitin ligase HDM2-mediated proteolysis. Zoledronic acid disrupts this NFATc2 stabilization pathway through two mechanisms, namely GSK-3β inhibition and induction of HDM2 activity. Upon nuclear accumulation, HDM2 targets unphosphorylated NFATc2 for ubiquitination at acceptor lysine residues Lys-684/Lys-897 and hence labels the factor for subsequent proteasomal degradation. Conversely, mutagenesis-induced constitutive serine phosphorylation (Ser-215, Ser-219, and Ser-223) of the SP2 domain prevents NFATc2 from HDM2-mediated ubiquitination and degradation and consequently rescues cancer cells from growth suppression by zoledronic acid. In conclusion, this study demonstrates a critical role of the GSK-3β-HDM2 signaling loop in the regulation of NFATc2 protein stability and growth promotion and suggests that double targeting of this pathway is responsible, at least to a significant part, for the potent and reliable anti-tumoral effects of zoledronic acid.

S100P-Binding Protein, S100PBP, Mediates Adhesion through Regulation of Cathepsin Z in Pancreatic Cancer Cells

Finding and Killing the CRABs of Pancreatic Cancer

Mechanistic Insights into Self-Reinforcing Processes Driving Abnormal Histogenesis During the Development of Pancreatic Cancer

Base excision repair (BER) is an essential pathway for pancreatic ductal adenocarcinoma (PDA) survival. Attempts to target this repair pathway have failed due to lack of tumor-selectivity and very limited efficacy. The NAD(P)H:Quinone Oxidoreductase 1 (NQO1) bioactivatable drug, ß-lapachone (ARQ761 in clinical form), can provide tumor-selective and enhanced synergy with BER inhibition. ß-Lapachone undergoes NQO1-dependent futile redox cycling, generating massive intracellular hydrogen peroxide levels and oxidative DNA lesions that stimulate poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation. Rapid NAD+/ATP depletion and programmed necrosis results. To identify BER modulators essential for repair of ß-lapachone-induced DNA base damage, a focused synthetic lethal RNAi screen demonstrated that silencing the BER scaffolding protein, XRCC1, sensitized PDA cells. In contrast, depleting OGG1 N-glycosylase spared cells from ß-lap-induced lethality and blunted PARP1 hyperactivation. Combining ß-lapachone with XRCC1 knockdown or methoxyamine (MeOX), an apyrimidinic/apurinic (AP)-modifying agent, led to NQO1-dependent synergistic killing in PDA, NSCLC, breast and head and neck cancers. OGG1 knockdown, dicoumarol-treatment or NQO1- cancer cells were spared. MeOX + ß-lapachone exposure resulted in elevated DNA double-strand breaks, PARP1 hyperactivation and TUNEL+ programmed necrosis. Combination treatment caused dramatic antitumor activity, enhanced PARP1-hyperactivation in tumor tissue, and improved survival of mice bearing MiaPaca2-derived xenografts, with 33% apparent cures. Significance: Targeting base excision repair (BER) alone has limited therapeutic potential for pancreatic or other cancers due to a general lack of tumor-selectivity. Here, we present a treatment strategy that makes BER inhibition tumor-selective and NQO1-dependent for therapy of most solid neoplasms, particularly for pancreatic cancer.

Pancreatic cancer will be the second leading cause of cancer-related deaths in the US by 2020, where 5-year survival is <6%. Current standard of care therapies offer little selectivity and high toxicity. Novel, tumor-selective approaches are desperately needed. Nearly 90% of pancreatic cancers have elevated levels (10- to 40-fold) NQO1 and we recently showed that beta-lapachone (beta-lap) was efficacious against pancreatic cancers in an NQO1-dependent manner (Li et al., Clin. Cancer Res., 2011). Beta-Lap is reduced by NQO1 like most quinones, but unlike most, its hydroquinone form is unstable and spontaneously redox cycles in a futile manner where one mole of beta-lap generates ∼120 moles of superoxide in two mins., inducing predominately DNA base and single strand break (SSB) damage. This results in PARP1 hyperactivation and programmed necrosis, killing NQO1+ cancer cells independent of: i, p53; ii, cell cycle; iii, all known oncogenic drivers; and iv, apoptotic/antiapoptotic gene expression (e.g., Bax, Bak, Bcl2). This ‘NQO1 bioactivatable drug’ is tumor-selective and a perfect candidate for improving efficacy of pancreatic cancer therapy. To improve its efficacy, we examined the synergistic effects of adding the AP site-modifying drug and base excision repair (BER) inhibitor, methoxyamine (MeOX), with beta-lap against NQO1 over-expressing pancreatic cancer cells. MeOX + beta-lap synergy resulted in: a, enhanced lethality of sublethal doses of beta-lap, reducing the shoulder (Dq), increasing the lethality rate (Do), and inducing apoptosis (TUNEL+) in NQO1+, but not in NQO1-, MIA PaCa-2 cells; b, increased DNA lesion formation; c, dramatic losses in ATP levels, with little recovery; and d, dramatic suppression of glycolysis. These data strongly suggests that MeOX enhances PARP1 hyperactivation and synergistic cell killing of beta-lap. Similar results were noted in shRNA-XRCC1 knockdown cells. Mechanistically, our data suggests that PARP1 detects MeOX-AP modified sites or SSBs, allowing PARP1 hyperactivation and synergistic cell death. Since MeOX is a nontoxic agent, and both agents are currently in clinical trials (i.e., beta-lap as Arq761, Arqule, Boston, MA), combination therapies for the treatment of pancreatic, as well as other NQO1 over-expressing solid cancers could be rapidly developed. An AACR Innovator Award from the George and June Block Foundation to DAB supported this work. Citation Format: Xiuquan Luo, Longshan Li, Xiumei Huang, Lifen Cao, Zachary Moore, Ralph Deberardinis, Rolf Brekken, Stanton Gerson, Lili Liu, David A. Boothman. Inhibiting base excision repair synergistically enhances beta-lapachone-mediated ‘kiss of death’ for tumor-selective therapy of pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3344. doi:10.1158/1538-7445.AM2013-3344

Pancreatic cancer is an aggressive cancer without currently effective treatment options. To develop effective therapies for pancreatic and other cancers, we developed bipartite Adenoviruses (Ads) that conditionally replicate in cancer cells and simultaneously express the cancer-specific apoptosis-inducing cytokine melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), termed Cancer Terminator Virus (CTV-M7). To enhance transduction of CTV-M7 in cancer cells in a Coxsackie-Adenovirus receptor (CAR) independent manner, a chimeric tropism-modified CTV-M7 was generated in which the Ad.5 fiber knob was replaced by the Ad.3 fiber knob (Ad.5/3-CTV-M7). This Ad displays enhanced infectivity in cancer cells with low as well as high CAR. Although mda-7 displays broad-spectrum anticancer properties, pancreatic ductal adenocarcinoma (PDAC) cells are intrinsically resistant to mda-7-mediated killing due to an mda-7 mRNA translational block. However, when Ad.5-mda-7 is combined with reactive oxygen species (ROS) inducers, there is a conversion of mda-7 mRNA into protein resulting in pancreatic cancer cell death. Hence, we employed perillyl alcohol (POH), which induces ROS and when combined with mda-7 results in profound killing of PDAC cells, a chemoprevention gene therapy (CGT) approach. ROS induced by POH results in phosphorylation of p70S6-Kinase, 4EBP-1 and eIF4E leading to formation of the pre-initiation complex of protein translation machinery causing an association of polysomes with weakly translated mda-7 mRNA, subsequently enhancing MDA-7 translation. We presently evaluated Ad.5/3-CTV-M7 plus POH as a therapy for PDAC by MTT assays and western blotting. Cell viability was reduced in pancreatic cancer cell lines irrespective of K-ras status following treatment with POH and infection with CTV-M7. This combination synergistically induced mda-7-mediated cancer-specific apoptosis by inhibiting anti-apoptotic Bcl-xL and Bcl-2 protein expression and inducing an endoplasmic reticulum stress response through induction of BiP/GRP-78, which was most evident in chimeric-modified CTV-M7-infected PDAC cells. Moreover, it was found that Ad.5/3-CTV-M7 in combination with POH sensitized MIA PaCa-2 cells over-expressing either Bcl-2 or Bcl-xL to mda-7-mediated apoptosis, demonstrating that CGT can overcome therapy resistance frequently seen in PDAC with elevated expression of these anti-apoptotic proteins. Treatment of MIA PaCa-2 overexpressing Bcl-xL cells established in both flanks of nude mice with POH and systemic administration of Ad.5/3.CTV-M7 using a ultrasound-targeted microbubble-destruction technique in tumors in one flank, resulted in tumor elimination on both flanks. These exciting studies support the potential of the CGT approach using POH and Ad.5/3-CTV-M7, for the therapy of currently intractable, therapy-resistant pancreatic cancers. Citation Format: Siddik Sarkar, Belal Azab, Bridget A. Quinn, Xuening Shen, Paul Dent, Alexander L. Klibanov, Luni Emdad, Swadesh K. Das, Devanand Sarkar, Paul B. Fisher. Chemoprevention gene therapy (CGT) approach for pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-315. doi:10.1158/1538-7445.AM2013-LB-315

Metabolic adaptations in tumors are necessary to balance the need for cellular energy supply, macromoleclar biosynthesis and maintenance of redox balance. A critical molecule produced as a result of this altered metabolism is nicotinamide adenine dinucleotide phosphate (NADPH). NADPH is a critical co-factor that provides reducing power to maintain cytoprotective concentrations of reduced glutathione against reactive oxygen species (ROS) that are produced during rapid growth and proliferation. In pancreatic cancers, NADPH can be formed by the NAD+ salvage pathway through the enzyme, Nicotinamide phosphoribosyltransferase (NamPT), as well as through the non-canonical metabolism of glutamine through glutaminase-1 (GLS1). While NamPT and GLS1 inhibitors have shown some anti-tumor activity in vitro and in vivo, these inhibitors lack tumor specificity and can have an extensive toxicity profile due to the requirement of NADPH synthesis in proliferating normal cells/tissue. We recently discovered that NAD(P)H:quinone oxidoreductase 1 (NQO1) levels were elevated 5- to 40-fold in >80% of pancreatic tumors vs associated normal tissue. As important, we noted that catalase levels were inversely expressed comparatively, elevated in normal and suppressed in tumor tissue. Thus, NQO1 represents a unique target to exploit for the therapeutic elimination of pancreatic cancers. While NQO1 is normally a detoxifying (Phase II) enzyme, we have discovered two unique classes of compounds that are ‘bioactivated’ in a futile redox cycle by the enzyme. NQO1 bioactivatable drugs, such as β-lapachone (β-lap) and deoxynyboquinone (DNQ), generate hydrogen peroxide as a mechanism to hyperactivate poly(ADP-ribose) polymerase 1 (PARP1), and to rapidly deplete NAD+ and ATP in a selective manner to kill tumors. Normal cells are protected due to low NQO1 and relatively high Catalase levels. We found that the tumor specificity and efficacy of NamPT or GLS1 inhibition can be greatly increased when small molecule NamPT inhibitors (e.g., FK866) or GLS1 inhibitors (e.g., BPTES) are used in combination with NQO1-bioactivatable drugs. With combination treatment, cells are primed for ROS-mediated damage due to reduced glutathione and NADPH levels; they are unable to recover ATP, NAD+, and NADPH synthesis even after only a 2 h exposure to NQO1 bioactivatable drugs, and they rapidly die through a caspase-independent, parthanatos (programmed necrosis) mechanism. Our findings indicate that NQO1-bioactivatable drugs may improve the sensitivities of clinical grade GLS1 and NamPT inhibitors in pancreatic cancer patients. This work was supported by an AACR/Pancreatic Cancer Action Network - George and June Block Foundation - Innovator Award and an NIH/NCI R01 CA102971 grant to DAB. Citation Format: Zachary Moore, Gaurab Chakrabarti, Costas Lyssiotis, Ralph Deberardinis, Boothman A. David. Modulating the NQO1-dependent ‘kiss of death’ mechanism of action of NQO1 bioactivatable drugs. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B47.

HSP60 is a mitochondrial localized quality control protein responsible for maintaining mitochondrial function. Although HSP60 is considered both a tumor suppressor and promoter in different types of cancer, the role of HSP60 in human pancreatic ductal adenocarcinoma (PDAC) remains unknown. In this study, we demonstrated that HSP60 was aberrantly expressed in human pancreatic cancer tissues and cell lines. Analysis of the Cancer Genome Atlas database revealed that HSP60 expression is positively correlated with pancreatic cancer. Further, knockdown of HSP60 attenuated pancreatic ductal cancer cell proliferation and migration/invasion, whereas ectopic expression of HSP60 increased tumorigenesis. Using an in vivo tumorigenicity assay, we confirmed that HSP60 promoted the growth of pancreatic ductal cancer cells. Functional analyses demonstrated that HSP60 plays a key role in the regulation of mitochondrial function. Mechanistically, both HSP60 knockdown and oxidative phosphorylation (OXPHOS) inhibition by metformin decreased Erk1/2 phosphorylation and induced apoptosis and cell cycle arrest, whereas Erk1/2 reactivation with EGF promoted cell proliferation. Intriguingly, in vitro ATP supplementation partially restored Erk1/2 phosphorylation and promoted proliferation in PDAC cells with HSP60 knockdown and OXPHOS inhibition. These results suggest that mitochondrial ATP is an important sensor of Erk1/2 regulated apoptosis and the cell cycle in PDAC cells. Thus, our findings indicate for the first time that HSP60 may serve as a novel diagnostic target of human pancreatic cancer, and that inhibition of mitochondrial function using drugs such as metformin may be a beneficial therapeutic strategy targeting pancreatic cancer cells with aberrant function of the HSP60/OXPHOS/Erk1/2 phosphorylation axis.

Pancreatic cancer is a lethal cancer with aggressive and invasive characteristics. By the time it is diagnosed, patients already have tumors extended to other organs and show extremely low survival rates. The gut microbiome is known to be associated with many diseases and its imbalance affects the pathogenesis of pancreatic cancer. In this study, we established an orthotopic, patient-derived xenograft model to identify how the gut microbiome is linked to pancreatic ductal adenocarcinoma (PDAC). Using the 16S rDNA metagenomic sequencing, we revealed that the levels of Alistipes onderdonkii and Roseburia hominis decreased in the gut microbiome of the PDAC model. To explore the crosstalk between the two bacteria and PDAC cells, we collected the supernatant of the bacteria or cancer cell culture medium and treated it in a cross manner. While the cancer cell medium did not affect bacterial growth, we observed that the A. onderdonkii medium suppressed the growth of the pancreatic primary cancer cells. Using the bromodeoxyuridine/7-amino-actinomycin D (BrdU/7-AAD) staining assay, we confirmed that the A. onderdonkii medium inhibited the proliferation of the pancreatic primary cancer cells. Furthermore, RNA-seq analysis revealed that the A. onderdonkii medium induced unique transcriptomic alterations in the PDAC cells, compared to the normal pancreatic cells. Altogether, our data suggest that the reduction in the A. onderdonkii in the gut microbiome provides a proliferation advantage to the pancreatic cancer cells. KEY POINTS: • Metagenome analysis of pancreatic cancer model reveals A. onderdonkii downregulation. • A. onderdonkii culture supernatant suppressed the proliferation of pancreatic cancer cells. • RNA seq data reveals typical gene expression changes induced by A. onderdonkii.

Introduction: Recent studies have demonstrated a clear association between smoking and the incidence of pancreatic ductal adenocarcinoma (PDAC); however, the effect of cigarette smoke in the activation of stem cell (SC) or cancer stem cell (CSC) genes and their involvement in the initiation and progression of PDAC have not yet been studied. It is well known that CSCs are responsible for the drug resistance and aggressiveness of the disease including PDAC. In this study, we investigated the effects of smoking on enrichment of SC/CSCs in pancreatic normal and ductal adenocarcinoma cells, and we also examined whether smoking can activate NF-kB signaling, which is in part leads to enrichment of CSC and induction of CSC markers in PDAC. Methods: Cigarette smoke extract (CSE) was prepared, and HPNE (Human pancreatic nestin positive cells) and Capan-1 pancreatic cancer (PC) cells were treated with CSE for up to ∼15 weeks. Side population (SP) were analyzed by Hoechst staining using Flow-cytomer, and various CSC markers such as PD2 (a stem cell maintenance marker), CD44, ALDH-1, SOX-9 (a multipotent SC marker) and Oct-3/4 (a pluripotent marker), and NF-kB signaling molecules were analyzed by western blotting. ALDH1+ cells, CD44+CD24+ CSCs and G0/G1 phase low cycling quiescent cells were analyzed by flow cytometer. An in-vitro sphere culture was also performed to further confirm the smoke induced CSC properties. Smoke exposed pancreatic tissues excised from unfloxed littermate control (LSL-K-Ras G12D) pancreatic tissue sections were immunostained for SOX-9 using immunohistochemistry (IHC), and for SOX9 and CD44 using immunofluorescence. Results: Our results showed increased SC/CSCs and more number of spheres by CSE treated cells as compared to their untreated controls and displayed elevated protein expressions of SC/CSC markers. We also observed an elevated CD44+CD24+ CSCs, increased ALDH1+ cells and increased G0/G1 low cycling quiescent cell population in CSE treated cells as compared to untreated controls. In addition, increased immunohistochemical staining for SOX9 and increased immunofluorescent signal for SOX-9 and CD44 were observed in smoke exposed animal tissues indicating that smoking may transform SOX-9+ multipotent SCs into SOX9+CD44+ CSCs. We also analyzed the expression levels of NF-kB signaling molecules in CSE treated HPNE and Capan-1 cells. As compared to their untreated controls, CSE treated cells showed elevated protein expression levels of phospho AKT, phospho RelA (SOX-9 promoter binding subunit of NF-kB complex) and phospho IKKα (a kinase that phosphorylates IKBα, an inhibitor of RelA) suggesting that smoking activates NF-kB signaling. Conclusion: Our results illustrate that smoking enriches SC/CSCs populations in normal pancreatic cells as well as in pancreatic cancer cells, and activates SOX9 through NF-kB signaling in PDAC. Citation Format: Ramakrishna Nimmakayala, Parthasarathy Seshacharyulu, Seema Chugh, Imayavaramban Lakshmanan, Satyanarayana Rachagani, Surinder K Batra, Moorthy P Ponnusamy. Smoking enriches cancer stem cell population and activates Sox9 through NF-kB signaling in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2490.

A18: HuR, an RNA binding protein, is critical for the DNA damage response in pancreatic cancer cells.