The BET inhibitor sensitivity is associated with the expression level of CDC25B in pancreatic cancer models

Abstract

Aim: Cell division cycle 25B (CDC25B) belongs to the CDC25 family of phosphatases that regulate cell cycle progression. CDC25B also contributes to tumor initiation and progression, but no connection between CDC25B levels and drug sensitivity in pancreatic cancer has been reported. Based on our finding that bromodomain and extraterminal domain (BET) inhibitors decrease levels of CDC25B, we aim to compare the sensitivity of models expressing contrasting levels of CDC25B to the BET inhibitor JQ1, in pancreatic cancer cell lines in vitro and in patient-derived xenograft (PDX) models of pancreatic ductal adenocarcinoma (PDAC) in vivo.

Methods: We compared the efficacy of the standard of care agent gemcitabine with the BET inhibitor JQ1, using alamarBlue assays to determine IC₅₀s of three pancreatic cancer cell lines in vitro. We used immunohistochemistry (IHC) and immunoblot (IB) to detect CDC25B. We also compared the effect of each agent on the progression of PDX models of PDAC in vivo with contrasting levels of CDC25B.

Results: Immunohistochemical data demonstrated that levels of CDC25B differed by ~2- to 5-fold in cell lines and PDX models used. In vitro data showed that the level of CDC25B paralleled sensitivity to JQ1. Similarly, in vivo data showed that tumors with high-level CDC25B were more sensitive to JQ1 than tumors with lower CDC25B. The combination of JQ1 + a pan CDC25 inhibitor was synergistic in gemcitabine-resistant Panc1.gemR cells that had relatively high levels of CDC25B expression compared to parent cells.

Conclusion: The data suggest that CDC25B may be an independent indicator of sensitivity to BET inhibitors and that CDC25B may contribute to gemcitabine insensitivity in this tumor type.

Keywords

Cell division cycle 25B (CDC25B) / pancreatic ductal adenocarcinoma (PDAC) / gemcitabine / patient-derived xenograft (PDX) models / BET inhibitor (BETi) / gemcitabine-resistant (gemR) models

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