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Transcriptional Inactivation of TP53 and the BMP Pathway Mediates Therapy-induced Dedifferentiation and Metastasis in Prostate Cancer

By Hyunho Han, Yan Wang, Josue Navarro Curto, Sreeharsha Gurrapu, Sara Laudato, Alekya Rumandla, Goutam Chakraborty, Xiaobo Wang, Hong Chen, Yan Jiang, Dhiraj Kumar, Emily G Caggiano, Boyu Zhang, Yan Ji, Sankar N Maity, Min Hu, Shanshan Bai, Ana Aparicio, Eleni Efstathiou, Christopher J. Logothetis, Nicholas Navin, Nora M Navone, Yu Chen, Filippo Giancotti

Posted 15 Apr 2021
bioRxiv DOI: 10.1101/2021.04.14.439569

Unsupervised clustering and deconvolution analysis identifies three intrinsic subtypes of Metastatic Castration-Resistant Prostate Cancer (M-CRPC): AR pathway-positive Prostate Cancer (ARPC), Neuro Endocrine Prostate Cancer (NEPC), and a novel subtype endowed with hybrid epithelial/mesenchymal (E/M) and luminal progenitor-like traits (Mesenchymal and Stem-like PC, MSPC). Analysis of large patient datasets and in vitro studies support the notion that MSPC originates from ARPC as a consequence of therapy-induced lineage plasticity. Intriguingly, AR blockade instigates two separate and complementary processes: 1) transcriptional silencing of TP53 and hence acquisition of hybrid E/M and stem-like traits; and 2) inhibition of the BMP-SMAD pathway, which promotes resistance to the pro-apoptotic and anti-proliferative effects of AR inhibition. MSPC cell lines and prostate adenocarcinoma cells reprogrammed in vitro to MSPC exhibit a marked dependency on HER2/3 signaling. Moreover, combinations of the panHER inhibitor neratinib with enzalutamide or the mTORC1 inhibitor MLN0128 exhibit efficacy in preclinical models of mixed ARPC/MSPC or MSPC, respectively. Collectively, these results identify a novel subtype of M-CRPC, trace its origin to therapy induced lineage plasticity, and reveal its dependency on HER2/3 signaling.

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