F. Blanco,1 M. Jimbo,1 N. Meisner Kober,2 E. Londin,1 I. Rigoutsos,1 M. V. Risbud,1 C. Yeo,1 J. Winter,1 P. McCue,1 J. Brody1; 1Thomas Jefferson University, Philadelphia, PA, 2Novartis Institutes for Biomedical Research, Basel, Switzerland
BACKGROUND: Pancreatic Ductal Adenocarcinoma will become the second leading cause of cancer-related deaths in the US by 2020. A recent Phase III randomized controlled trial revealed a four month overall survival benefit in metastatic PDA with FOLFIRINOX (Folinic acid, 5FU, Irinotecan, and Oxaliplatin) compared to gemcitabine, the standard of care. However, the clinical efficacy of FOLFIRINOX is limited by acquired tumor-associated drug resistance. We have identified a novel drug resistance mechanism driven by the hypoxia-inducible pro-oncogenic kinase PIM1. Here, we determined the potential of targeting PIM1 to enhance therapeutic responses in PDA.
METHODS: To model hypoxia, PDA cells were incubated in 1% O2 and responses to 5FU or oxaliplatin assessed to obtain IC50 doses. Stabilizing interactions between the RNA-binding protein HuR and PIM1 mRNA were quantified by binding and confirmed by immunohistochemistry in resected PDAs (n=91). The contribution of HuR-mediated regulation of PIM1 to resistance to 5FU or oxaliplatin in hypoxia was examined using MS444 (Novartis), a novel, low-molecular-weight HuR inhibitor.
RESULTS: Hypoxia activates HuR, which binds and stabilizes PIM1 mRNA. This regulatory interaction amplifies PIM1 mRNA translation and protein overexpression. In turn, PIM1 overexpression enhances DNA repair, overriding DNA damage induced by cytotoxic agents. Inhibition of HuR by MS444 abrogates hypoxia-induced PIM1 overexpression, enhancing PDA cell sensitivity to oxaliplatin and 5FU (P<0.01).
CONCLUSION: The mRNA-stability factor HuR post-transcriptionally regulates PIM1 to promote hypoxia-induced chemoresistance. Ongoing pre-clinical studies will evaluate pharmacologic inhibition of HuR as a novel modality to enhance the therapeutic value of FOLFIRINOX for the treatment of metastatic PDA.