Combined BET bromodomain and DNA methyltransferase inhibition targets critical survival pathways in transdifferentiated prostate cancer
William K. Storck, Diana Flores, Anbarasu Kumaraswamy, Zhi Duan, Shrabastee Chakraborty, Chao Zhang, Eva Rodansky, Dhruv Khokhani, Olivia A. Swaim, Karan Bedi, Raymond G. Cavalcante, Canping Chen, Faming Zhao, Ya-Mei Hu, Zheng Xia, Ryan J. Rebernick, Marcin Cieslik, Rahul Mannan, Somnath Mahapatra, Arul M. Chinnaiyan, Aaron M. Udager, Joshua A. Kuleape, Catherine R. Alumkal, Hannah N. Beck, Peter S. Nelson, Colm Morrissey, Michael C. Haffner, Leigh Ellis, Yuzhuo Wang, Joel A. Yates, Joshi J. Alumkal
William K. Storck, Diana Flores, Anbarasu Kumaraswamy, Zhi Duan, Shrabastee Chakraborty, Chao Zhang, Eva Rodansky, Dhruv Khokhani, Olivia A. Swaim, Karan Bedi, Raymond G. Cavalcante, Canping Chen, Faming Zhao, Ya-Mei Hu, Zheng Xia, Ryan J. Rebernick, Marcin Cieslik, Rahul Mannan, Somnath Mahapatra, Arul M. Chinnaiyan, Aaron M. Udager, Joshua A. Kuleape, Catherine R. Alumkal, Hannah N. Beck, Peter S. Nelson, Colm Morrissey, Michael C. Haffner, Leigh Ellis, Yuzhuo Wang, Joel A. Yates, Joshi J. Alumkal
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Research Article Cell biology Oncology

Combined BET bromodomain and DNA methyltransferase inhibition targets critical survival pathways in transdifferentiated prostate cancer

Abstract

Lineage plasticity, or transdifferentiation, is increasingly recognized as a resistance mechanism to androgen receptor (AR) inhibition in prostate cancer. Lineage plasticity is characterized by loss of AR signaling and epithelial differentiation, along with activation of stemness-associated pathways, epithelial-mesenchymal transition, or alternative differentiation programs such as neuroendocrine prostate cancer (NEPC). Loss of the tumor suppressors TP53 and RB1 is common in tumors exhibiting lineage plasticity; however, the mechanisms by which TP53/RB1 loss promotes this phenotype remain poorly understood, and effective treatments are limited. Using multiomic profiling of TP53/RB1-loss prostate cancer models, we identified alterations in chromatin accessibility, DNA methylation, and gene expression associated with lineage plasticity. Importantly, many pathways activated upon TP53/RB1 loss could be blocked through BET bromodomain inhibition. TP53/RB1-deficient cells also harbored widespread DNA methylation changes that silenced pathways linked with restraining lineage plasticity. Combined BET bromodomain and DNA methyltransferase (DNMT) inhibition was more effective than single-agent treatment in suppressing growth of TP53/RB1-loss models exhibiting a stem-like or NEPC program. This was partly explained by abrogation of discrete lineage plasticity pathways modulated by each agent. Altogether, our work suggests combined BET bromodomain and DNMT inhibition is a promising therapeutic approach for prostate tumors exhibiting lineage plasticity.

Authors

William K. Storck, Diana Flores, Anbarasu Kumaraswamy, Zhi Duan, Shrabastee Chakraborty, Chao Zhang, Eva Rodansky, Dhruv Khokhani, Olivia A. Swaim, Karan Bedi, Raymond G. Cavalcante, Canping Chen, Faming Zhao, Ya-Mei Hu, Zheng Xia, Ryan J. Rebernick, Marcin Cieslik, Rahul Mannan, Somnath Mahapatra, Arul M. Chinnaiyan, Aaron M. Udager, Joshua A. Kuleape, Catherine R. Alumkal, Hannah N. Beck, Peter S. Nelson, Colm Morrissey, Michael C. Haffner, Leigh Ellis, Yuzhuo Wang, Joel A. Yates, Joshi J. Alumkal

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Figure 6

BETi and DNMTi combination treatment leads to superior growth suppression in lineage plasticity models in vivo.

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BETi and DNMTi combination treatment leads to superior growth suppressio...
(A and C) Growth of LTL331R (26) PDXs treated with vehicle (n = 12), ZEN (50 mg/kg; n = 12), dAZA (0.8 mg/kg; n = 12), or ZEN plus dAZA (n = 15) (A) and TKO tumors treated with vehicle (n = 11), ZEN (50 mg/kg; n = 11), dAZA (0.4 mg/kg; n = 10), or ZEN plus dAZA (n = 11) (C) are shown. The treatment schedule for the duration of each study is indicated by colored bars beneath the tumor growth data. Data shown are the mean ± SEM. Statistical significance was determined using 2-way ANOVA followed by Tukey’s multiple-comparison test. (B and D) LTL331R (26) PDXs (B) and TKO tumors (D) harvested 5 days after treatment start were sectioned and stained with H&E or antibodies against the indicated proteins. Arrowheads indicate positively stained nuclei. Scale bar: 20 μm. Quantification of immunostaining is shown on the right and presented as floating bars representing the minimum and maximum values with the mean indicated (n = 3 for each treatment condition). Statistical significance was determined using 1-way ANOVA with Benjamini-Hochberg multiple testing correction. *P < 0.05; **P < 0.01.