Androgen receptor-induced integrin α6β1 and Bnip3 promote survival and resistance to PI3K inhibitors in castration-resistant prostate cancer

Abstract

The androgen receptor (AR) is the major driver of prostate cancer growth and survival. However, almost all patients relapse with castration-resistant disease (CRPC) when treated with anti-androgen therapy. In CRPC, AR is often aberrantly activated independent of androgen. Targeting survival pathways downstream of AR could be a viable strategy to overcome CRPC. Surprisingly, little is known about how AR drives prostate cancer survival. Furthermore, CRPC tumors in which Pten is lost are also resistant to eradication by PI3K inhibitors. We sought to identify the mechanism by which AR drives tumor survival in CRPC to identify ways to overcome resistance to PI3K inhibition. We found that integrins α6β1 and Bnip3 are selectively elevated in CRPC downstream of AR. While integrin α6 promotes survival and is a direct transcriptional target of AR, the ability of AR to induce Bnip3 is dependent on adhesion to laminin and integrin α6β1-dependent nuclear translocation of HIF1α. Integrins α6β1 and Bnip3 were found to promote survival of CRPC cells selectively on laminin through the induction of autophagy and mitophagy. Furthermore, blocking Bnip3 or integrin α6β1 restored sensitivity to PI3K inhibitors in Pten-negative CRPC. We identified an AR driven pathway that cooperates with laminin and hypoxia to drive resistance to PI3K inhibitors. These findings can help explain in part why PI3K inhibitors have failed in clinical trials to overcome AR-dependent CRPC.

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Fig. 1: Integrin α6β1 and Bnip3 are elevated in CRPC.
Fig. 2: Androgen indirectly induces Bnip3 through integrin α6β1 and HIF1α.
Fig. 3: AR confers resistance to PI3K inhibition via integrin α6β1.
Fig. 4: AR confers resistance to PI3K inhibition via Bnip3.
Fig. 5: Androgen-induced autophagy in CRPC requires laminin.
Fig. 6: Androgen-induced autophagy requires integrin α6 and Bnip3.
Fig. 7: Bnip3 LC3-interaction domain is required to promote resistance to PI3K inhibition.

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Acknowledgements

We would like to thank Drs. Sander Frank and Don Tindall for feedback and constructive suggestions and Penny Berger for technical expertise. Special thanks to Scott Peterson for supplying the PX-866. These studies were supported by funding from NIH/NCI R01CA154835, P30CA023074 (CKM, SSG, EAN, and VVS), and the Van Andel Research Institute. Additional support was provided by NIH/NCI CA159406 (AC).

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Correspondence to Cindy K. Miranti.

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Nollet, E.A., Cardo-Vila, M., Ganguly, S.S. et al. Androgen receptor-induced integrin α6β1 and Bnip3 promote survival and resistance to PI3K inhibitors in castration-resistant prostate cancer. Oncogene (2020). https://doi.org/10.1038/s41388-020-1370-9

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