Background: BBI-608 has been shown to modulate multiple oncogenic cellular pathways which are often constitutively active in pancreatic ductal adenocarcinoma (PDAC). Among these are key mediators of DNA repair and cellular survival pathways. We hypothesized that BBI-608 would sensitize PDAC cells to chemoradiotherapy.

Methods: The combined effects of BBI-608 and chemoradiotherapy (5-FU + IR) were evaluated in human (MIA PaCa-2) and murine (PANC-02) PDAC cell lines using a Br-dU cell proliferation assay. To elucidate the mechanism of action, effects on the expression of DNA damage and repair (pATM, γ-H2AX, p53; pATR, and Rad51) molecules were examined by Western blot. Apoptosis was assessed via Annexin V staining and flow cytometric analysis to evaluate mechanism of cell death following treatment of MIA PaCa-2 and PANC-02 cell lines. The in vivo activity of BBI-608, 5-FU + IR, alone and in combination, were evaluated in C57BL/6 mice bearing subcutaneous PANC-02 tumors.

Results: The combination of BBI-608 and chemoradiotherapy significantly decreased (p<0.001) cell proliferation and induced Annexin V positive cells in both MIA PaCa-2 and PANC-02 cell lines. BBI-608 and chemoradiotherapy also decreased the activation of pATR, MDM2, and Rad51 and increased pATM, γ-H2AX and p53. Administration of BBI-608 potentiated the effects of chemoradiotherapy in vivo in mice bearing subcutaneous PANC-02 tumors as measured by tumor volume.

Conclusion: These data identify a role for BBI-608 as a modulator of DNA damage and apoptosis. These effects enhanced the efficacy of chemoradiotherapy in cell lines and in vivo models of PDAC and provide rationale for continued investigation in the pre-clinical and clinical setting.

Note: This abstract was not presented at the meeting.

Citation Format: Batoul Farran, Ganji P. Nagaraju, Sneha G. Shipra, Shipra R. Bethi, Gregory B. Lesinski, Bassel El-Rayes. BBI-608 modulates DNA repair pathways, induces apoptosis and impacts response to 5-Fluorouracil and ionizing radiation in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 713.