Abstract
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 (GEM) and CHK1 inhibitors SCH900776 and MU380 in docetaxel‐resistant (DR) mCRPC. Given the results, both CHK1 inhibitors significantly potentiated the sensitivity to GEM in a panel of chemo‐naïve and matched DR PCa cell lines under 2D conditions. MU380 exhibited a stronger synergistic effect with GEM than clinical candidate SCH900776. MU380 alone or in combination with GEM significantly reduced spheroid size and increased apoptosis in all patient‐derived xenograft 3D cultures, with a higher impact in DR models. Combined treatment induced premature mitosis from G1 phase resulting in the mitotic catastrophe as a prestage of apoptosis. Finally, treatment by MU380 alone, or in combination with GEM, 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 GEM in DR mCRPC models. This approach might allow for dose reduction of GEM and thereby minimize undesired toxicity and may represent a therapeutic option for patients with incurable DR mCRPC.
Highlights
Prostate cancer (PCa) represents one of the most heterogeneous and clinically common malignancies in men
Considering the data from drug screenings addressing the sensitivity of all models to various chemotherapy agents with different mechanisms of action and molecular mechanism of Checkpoint kinase 1 (CHK1) activation triggered by apical kinases ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and Rad3-related (ATR) after the induction of DNA damage [26], we selected GEM as a suitable chemotherapy drug for the combined treatment (Figs S1–S3)
The combined treatment with GEM and MU380 or SCH900776 was more effective than GEM monotherapy in a majority of DR and control models, while the monotherapy by MU380 or SCH900776 had no impact on cell viability (Fig. 1D,E, Fig. S4 and Table S2)
Summary
Prostate cancer (PCa) represents one of the most heterogeneous and clinically common malignancies in men. Despite a high initial effectivity of androgen deprivation therapy in localized disease with medium and high risk, nearly half of the patients experience progression to the incurable and lethal form termed metastatic castration-resistant PCa (mCRPC) [1]. Treatment options for this advanced stage of the disease are rather limited. Docetaxel has been used as the most effective treatment strategy for mCRPC patients since 2004 It gives only modest survival benefit with most patients invariably progressing due to acquired or inherent drug resistance [2,3]. Due to the very low efficacy of chemotherapeutics, prolonged anamnesis and resistance, the follow-up therapies may pose more risk than help, indicating that identification of new druggable targets in mCRPC is crucial for the development of more efficient therapies
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