Abstract A23: Characterization of novel molecular vulnerabilities provoking replicative and energetic stresses in pancreatic cancer cells

Pancreatic cancer (PDAC) remains a deadly disease with no cure. In this dismal context, we demonstrated that non-viral gene therapy to sensitize cancer cells to chemotherapy was safe and feasible, and offers therapeutic benefit in patients (Thergap trial 2010-2012). However, alternative molecular pathways must be targeted to relieve resistance to treatment for best therapeutic benefit. We identified cytidine deaminase (CDA) that catalyzes the hydrolytic deamination of cytidine and deoxycytidine to uridine and deoxyuridine, as overexpressed (i) in cohorts of patients resisting to gemcitabine, (ii) in PDAC as compared to normal parenchyma, and (iii) in patients receiving gene therapy. Targeting CDA using genetic tools sensitizes cancer cells to chemotherapy both in vitro and in vivo, with very high efficacy in preclinical models of cancer. On the other hand, loss of CDA per se unexpectedly alters cell proliferation, cell cycle progression and tumor growth in vivo, when more than half of mice engrafted with CDA-null human pancreatic cancer cells remained free of tumors nor developed metastasis. Using a multi-omics approach, we found that both pyrimidine and purine levels are decreased, inducing replicative stress hallmarks in CDA-null cells, and TCA cycle is altered, strongly suggesting mitochondrial dysfunction, as we further demonstrate decreased mitochondrial ATP and down expression of key proteins of the mitochondrial OXPHOS complexes and β-oxidation. Consequently, mitochondrial ROS are elevated with major changes in the redox balance in PDAC cells. Remarkably, tumor cells retaliate using compensatory mechanisms resembling Pasteur effect with elevated lactate levels. These compensatory mechanisms served as secondary targets to (i) further strengthen the inhibition of cell proliferation and migration seen in CDA-null cells, and (ii) annihilate potential mechanisms of resistance to treatment. Taken together, our aforementioned results demonstrate for the first time that targeting CDA, an enzyme primarily thought to be restricted to the pyrimidine salvage pathway, strongly alters PDAC proliferation and tumor progression, via massive modification of cancer cell metabolism and alteration of cell cycle, in the absence of chemotherapy. To the best of our knowledge, the crosstalk between replicative and energetic pathways has been thus far totally underexplored in cancer. As specific inhibitors of CDA are underway, we postulate that PDAC rewiring following CDA targeting can be considered exploitable Achille’s eel or vulnerabilities for novel, DNA and metabolic-based, synthetic lethality strategies and the promise of targeted-approaches with high efficacy for PDAC therapy. Note: This abstract was not presented at the conference. Citation Format: Marion Gayral, Audrey Frances, Estelle Saland, Hubert Lulka, Naima Hanoun, Anthony Lemarié, Laetitia Ligat, Nathalie Saint-Laurent, Frédéric Lopez, Louis Buscail, Jean-Emmanuel Sarry, Pierre Cordelier.{Authors}. Characterization of novel molecular vulnerabilities provoking replicative and energetic stresses in pancreatic cancer cells. [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 A23.