Pharmacological inhibition of the Notch pathway enhances the efficacy of androgen deprivation therapy for prostate cancer

Abstract

Although androgen deprivation therapy (ADT) is a standard treatment for metastatic prostate cancer, this disease inevitably recurs and progresses to ADT-resistant stage after this therapy. Accordingly, understanding the mechanism of resistance to ADT and finding new approach to enhance the efficacy of ADT may provide a major benefit to PCa patients. In our study, we found upregulated expression of Notch receptors is positive associated with ADT-resistance progression. Using fluorescent Notch signaling reporter system, we observed that endogenous Notch signaling could be activated after treatment of androgen deprivation in LNCaP cells via activation of Notch3. In addition, exogenous activation of the Notch signaling though Dox-induced overexpression of any Notch intracellular domains (NICD1-4) could enhance the resistance of PCa cells to ADT under ex vivo 3D culture conditions and upregulate expression of ADT resistance-associated phospho-p38 and Bcl-2 in LNCaP cells. As a result, pharmacological inhibition of the Notch pathway using γ-secretase inhibitor (GSI), DAPT, downregulated both phospho-p38 and Bcl-2 expression and significantly enhanced the efficacy of ADT in androgen sensitive PCa cells with impaired proliferation and 3D colony formation, increased apoptosis and remarkable inhibition of tumor growth in murine subcutaneous xenograft model. These results indicate that activated Notch signaling contributes to ADT resistance, and suggest that inhibition of the Notch pathway may be a promising adjuvant therapy of ADT for PCa.

Notch3 promotes prostate cancer-induced bone lesion development via MMP-3

“…Recent studies demonstrate that Notch3 is involved in normal prostate development where it is required for luminal cell differentiation (11,14,15). Furthermore, elevated Notch3 expression positively correlates with prostate cancer progression, recurrence, and drug resistance (16)(17)(18)(19)(20). In metastatic breast cancer, Jag-1 in tumor cells activates Notch signaling in osteoblasts to stimulate osteoclastogenesis in osteolytic bone lesions, while Notch3 is induced in tumor cells by osteoblasts (21,22).…”

Targeted Notch1 inhibition with a Notch1 antibody, OMP‐A2G1, decreases tumor growth in two murine models of prostate cancer in association with differing patterns of DNA damage response gene expression

“…Furthermore, Notch inhibition was shown to overcome resistance to androgen deprivation in PCa cells, strengthening the link between Notch and AR signaling. 31 VCaP AR expression may explain the lack of difference in proliferation of OMP-A2G1-treated tumors. Another possibility is the ERG expression present in VCaP but not DU145.…”

Notch signalling is a potential resistance mechanism of progenitor cells within patient‐derived prostate cultures following ROS‐inducing treatments

“…Therefore, elucidating the mechanisms of resistance to ADT is necessary. Three recent studies have shown that Notch signalling can contribute to resistance to enzalutamide (androgen receptor antagonist) [46] and that Notch inhibition combined with ADT can cause a synergistic therapeutic effect [47,48]. In addition, Notch signalling has also been implicated in docetaxel resistance [49].…”