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A synthetic lethal screen for Snail-induced enzalutamide resistance identifies JAK/STAT signaling as a therapeutic vulnerability in prostate cancer

Ware, KE and Thomas, BC and Olawuni, PD and Sheth, MU and Hawkey, N and Yeshwanth, M and Miller, BC and Vietor, KJ and Jolly, MK and Kim, SY and Armstrong, AJ and Somarelli, JA (2023) A synthetic lethal screen for Snail-induced enzalutamide resistance identifies JAK/STAT signaling as a therapeutic vulnerability in prostate cancer. In: Frontiers in Molecular Biosciences, 10 .

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Official URL: https://doi.org/10.3389/fmolb.2023.1104505


Despite substantial improvements in the treatment landscape of prostate cancer, the evolution of hormone therapy-resistant and metastatic prostate cancer remains a major cause of cancer-related death globally. The mainstay of treatment for advanced prostate cancer is targeting of androgen receptor signaling, including androgen deprivation therapy plus second-generation androgen receptor blockade (e.g., enzalutamide, apalutamide, darolutamide), and/or androgen synthesis inhibition (abiraterone). While these agents have significantly prolonged the lives of patients with advanced prostate cancer, is nearly universal. This therapy resistance is mediated by diverse mechanisms, including both androgen receptor-dependent mechanisms, such as androgen receptor mutations, amplifications, alternative splicing, and amplification, as well as non-androgen receptor-mediated mechanisms, such as lineage plasticity toward neuroendocrine-like or epithelial-mesenchymal transition (EMT)-like lineages. Our prior work identified the EMT transcriptional regulator Snail as critical to hormonal therapy resistance and is commonly detected in human metastatic prostate cancer. In the current study, we sought to interrogate the actionable landscape of EMT-mediated hormone therapy resistant prostate cancer to identify synthetic lethality and collateral sensitivity approaches to treating this aggressive, therapy-resistant disease state. Using a combination of high-throughput drug screens and multi-parameter phenotyping by confluence imaging, ATP production, and phenotypic plasticity reporters of EMT, we identified candidate synthetic lethalities to Snail-mediated EMT in prostate cancer. These analyses identified multiple actionable targets, such as XPO1, PI3K/mTOR, aurora kinases, c-MET, polo-like kinases, and JAK/STAT as synthetic lethalities in Snail+ prostate cancer. We validated these targets in a subsequent validation screen in an LNCaP-derived model of resistance to sequential androgen deprivation and enzalutamide. This follow-up screen provided validation of inhibitors of JAK/STAT and PI3K/mTOR as therapeutic vulnerabilities for both Snail+ and enzalutamide-resistant prostate cancer.

Item Type: Journal Article
Publication: Frontiers in Molecular Biosciences
Publisher: Frontiers Media S.A.
Additional Information: The copyright for this article belongs to the author.
Keywords: collateral sensitivity; drug resistance; epithelial plasticity; high-throughput screens; hormone therapy resistance
Department/Centre: Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Date Deposited: 03 Jul 2023 07:12
Last Modified: 03 Jul 2023 07:12
URI: https://eprints.iisc.ac.in/id/eprint/82137

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