Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance

By Sheng-Yu Ku, S. Rosario, Yanqing Wang, P. Mu, M. Seshadri, Zachary Goodrich, Maxwell M. Goodrich, David P. Labbé, E. C. Gomez, Jian-mei Wang and 7 more. Science, 2017

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Evading cancer drugs by identity fraud Prostate cancer growth is fueled by male hormones called androgens. Drugs targeting the androgen receptor (AR) are initially efficacious, but most tumors eventually become resistant (see the Perspective by Kelly and Balk). Mu et al. found that prostate cancer cells escaped the effects of androgen deprivation therapy through a change in lineage identity. Functional loss of the tumor suppressors TP53 and RB1 promoted a shift from AR-dependent luminal epithelial cells to AR-independent basal-like cells. In related work, Ku et al. found that prostate cancer metastasis, lineage switching, and drug resistance were driven by the combined loss of the same tumor suppressors and were accompanied by increased expression of the epigenetic regulator Ezh2. Ezh2 inhibitors reversed the lineage switch and restored sensitivity to androgen deprivation therapy in experimental models. Science, this issue p. 84, p. 78; see also p. 29 Prostate cancer cells escape androgen deprivation therapy by morphing into a cell type that does not require androgens. Prostate cancer relapsing from antiandrogen therapies can exhibit variant histology with altered lineage marker expression, suggesting that lineage plasticity facilitates therapeutic resistance. The mechanisms underlying prostate cancer lineage plasticity are incompletely understood. Studying mouse models, we demonstrate that Rb1 loss facilitates lineage plasticity and metastasis of prostate adenocarcinoma initiated by Pten mutation. Additional loss of Trp53 causes resistance to antiandrogen therapy. Gene expression profiling indicates that mouse tumors resemble human prostate cancer neuroendocrine variants; both mouse and human tumors exhibit increased expression of epigenetic reprogramming factors such as Ezh2 and Sox2. Clinically relevant Ezh2 inhibitors restore androgen receptor expression and sensitivity to antiandrogen therapy. These findings uncover genetic mutations that enable prostate cancer progression; identify mouse models for studying prostate cancer lineage plasticity; and suggest an epigenetic approach for extending clinical responses to antiandrogen therapy.

Subfields: Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/8225552432e9faddfd2c9e180b8308e578d060d4

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Citations in the corpus

Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling (2017, background): “While AR repression can allow for cellular reprogramming and transdifferentiation to NE carcinoma (Ku et al., 2017; Zou et al., 2017), our results indicate that the acquisition of NE characteristics may represent a continuum of differentiation from ARPC to DNPC to NEPC, although the acquisition of…”
Genomic correlates of clinical outcome in advanced prostate cancer (2019, background): “We also confirmed co-occurrence between alterations in TP53 and RB1, known to occur at high frequency in neuroendocrine cancers (7, 9), and to confer aggressive behavior in prostate cancer models (18, 19).”
Genetics and biology of prostate cancer (2018, background): “Third, preclinical models have demonstrated that AR+ adenocarcinoma can transdifferentiate into AR-independent NEPC or small cell carcinoma; moreover, genes such as MYCN, BRN2 (also called POU3F2), SOX2, AURKA, and EZH2 have been shown to play a critical role in these androgen-insensitive tumors, an”