1. Transcriptional Inactivation of TP53 and the BMP Pathway Mediates Therapy-induced Dedifferentiation and Metastasis in Prostate Cancer
- Author
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Nora M. Navone, Mickey C.T. Hu, Yongying Jiang, Huiqin Chen, Dhiraj Kumar, Hyunho Han, Ana Aparicio, Shanshan Bai, Rumandla A, Curto J, Xiaoping Wang, Bingnan Zhang, Christopher J. Logothetis, Caggiano E, Sankar N. Maity, Sara Laudato, Eleni Efstathiou, Goutam Chakraborty, Filippo G. Giancotti, Yuanxin Wang, Nicholas Navin, Yuan Ji, Ye-Guang Chen, and Sreeharsha Gurrapu
- Subjects
Mesenchymal stem cell ,mTORC1 ,Biology ,medicine.disease ,Metastasis ,chemistry.chemical_compound ,Prostate cancer ,chemistry ,Cell culture ,Neratinib ,medicine ,Cancer research ,Gene silencing ,Enzalutamide ,medicine.drug - Abstract
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.
- Published
- 2021