The CHK1 inhibitor MU380 significantly increases the sensitivity of human docetaxel-resistant prostate cancer cells to gemcitabine through the induction of mitotic catastrophe.

As treatment options for patients with incurable metastatic castration-resistant prostate cancer (mCRPC) are considerably limited, novel effective therapeutic options are needed. Checkpoint kinase 1 (CHK1) is a highly conserved protein kinase implicated in the DNA damage response (DDR) pathway that prevents the accumulation of DNA damage and controls regular genome duplication. CHK1 has been associated with prostate cancer (PCa) induction, progression, and lethality, hence CHK1 inhibitors SCH900776 (also known as MK-8776) and the more effective SCH900776 analog MU380 may have clinical applications in the therapy of PCa. Synergistic induction of DNA damage with CHK1 inhibition represents a promising therapeutic approach that has been tested in many types of malignancies, but not in chemoresistant mCRPC. Here we report, that such therapeutic approach may be exploited using the synergistic action of the antimetabolite gemcitabine and CHK1 inhibitors SCH900776 and MU380 in docetaxel-resistant mCRPC. Given the results, both CHK1 inhibitors significantly potentiated the sensitivity to gemcitabine in a panel of chemo-naive and matched docetaxel-resistant PCa cell lines under 2D conditions. MU380 exhibited a stronger synergistic effect with gemcitabine than clinical candidate SCH900776. MU380 alone or in combination with gemcitabine significantly reduced spheroid size and increased apoptosis in all patient-derived xenograft 3D cultures, with a higher impact in docetaxel-resistant models. Combined treatment induced premature mitosis from G1 phase resulting in the mitotic catastrophe as a pre-stage of apoptosis. Finally, treatment by MU380 alone, or in combination with gemcitabine, significantly inhibited tumor growth of both PC339-DOC and PC346C-DOC xenograft models in mice. Taken together, our data suggest that metabolically robust and selective CHK1 inhibitor MU380 can bypass docetaxel resistance and improve the effectiveness of gemcitabine in docetaxel-resistant mCRPC models. This approach might allow for dose reduction of gemcitabine and thereby minimize undesired toxicity and may represent a therapeutic option for patients with incurable docetaxel-resistant mCRPC.