Abstract 555: Mitochondrial fusion exerts KRAS-dependent therapeutic synergy with gemcitabine/nab-paclitaxel in preclinical models of pancreatic cancer
Authors: Nguyen Nicholas D. , Yu Meifang , Fujimoto Tara N. , Delahoussaye Abagail , Huang Yanqing , Estrada Manuel A. , Taniguchi Cullen M. 
Published: September 2020

Background: Pancreatic ductal adenocarcinoma (PDAC) is driven by activating Kras mutations which cause a fragmented mitochondrial phenotype. We recently demonstrated that leflunomide, an FDA-approved drug for rheumatoid arthritis, could be repurposed for pancreatic cancer therapy. The mode of action is through the activation of mitochondrial fusion, which inhibits PDAC growth in a KRAS-dependent fashion. Leflunomide also has the off-target effect of inhibiting dihydroorotate dehydrogenase (DHODH), which is critical for pyrimidine biosynthesis. Gemcitabine is part of the standard of care for pancreatic cancer and also inhibits nucleoside biosynthesis. Accordingly, we hypothesized that leflunomide might synergize with gemcitabine chemotherapy to further improve outcomes. In this pre-clinical study, we attempt to provide proof-of-concept for combining leflunomide with gemcitabine/nab-paclitaxel, the current gold standard for PDAC, in order to characterize a synergistic effect and to provide evidence for potentially repurposing the drug for clinical use.

Methods: We heterotopically implanted patient-derived pancreatic cancer cell lines with an activating KRAS mutations (MDA-PATC148) or WT KRAS (MDA-PATC153) into the flanks of immunocompromised (NOD-SCID) mice. The tumors were grown to 5mm in size then assigned to one of four treatment groups: (1) vehicle control, (2) gemcitabine/nab-paclitaxel only, and (3) leflunomide + gemcitabine/nab-paclitaxel. Leflunomide was dosed at 20 mg/kg and given concurrently with gemcitabine and nab-paclitaxel. Gemcitabine was administered IP 2x/week at 100 mg/kg and nab-paclitaxel given once per week by tail vein at 10 mg/kg.

Results: The combination of leflunomide with gemcitabine/nab-paclitaxel synergistically impeded tumor proliferation and reduced the median tumor volume by more than 50% when compared to vehicle (102.6 vs. 294.8 mm3, ****P-value &lt; 0.0001 by Mann-Whitney U test) or gemcitabine/nab-paclitaxel only group (102.6 mm3 vs. 211.7 mm3, **P-value &lt; 0.01 by Mann-Whitney U test) in KRAS mutant PATC148 mice. Interestingly, the addition of leflunomide to gemcitabine/nab-paclitaxel did not further improve tumor responses in KRAS wild-type PATC153 tumors, suggesting a dependence on mutant KRAS for therapeutic efficacy of the repurposed mitochondrial fusion actiator, leflunomide.

Conclusions: Leflunomide exhibits therapeutic synergy with standard-of-care gemcitabine/nab-paclitaxel in patient-derived PDAC lines that harbor KRAS mutations, but are ineffective in KRAS WT lines, suggesting that this combination might be effective not only in PDAC, but in other cancer with mutant KRAS, such as cancers of colon, lung, or bile ducts.

Citation Format: Nicholas D. Nguyen, Meifang Yu, Tara N. Fujimoto, Abagail Delahoussaye, Yanqing Huang, Manuel A. Estrada, Cullen M. Taniguchi. Mitochondrial fusion exerts KRAS-dependent therapeutic synergy with gemcitabine/nab-paclitaxel in preclinical models of pancreatic cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 555.