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

Abstract

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.

The Expanding World of N-MYC–Driven Tumors

“…49,118,119). The induction of lineage plasticity by N-MYC is also consistent with data from prostate epithelial cells engineered with a loss of RB1 or TP53 (120)(121)(122). A lineage switch driven by N-MYC induction appears to afford the tumor cells the ability to escape cell death induced by anti-AR therapy.…”

“…As noted above, EZH2 has been shown to cooperate with N-MYC as a transcriptional coregulator to drive CRPC toward an NEPC phenotype (46). Treatment with EZH2 inhibitors reverses N-MYC-driven target gene expression and abrogates tumor cell growth driven either by N-MYC (46) or other drivers of the NEPC phenotype (120,121). Given the availability of EZH2 inhibitors that are now in phase I clinical trials for advanced solid tumors (e.g., NCT02082977), this characterization will potentially provide a rationale for further clinical development for patients with N-MYC-overexpressed NEPC and CRPC.…”

“…As suggested in ref. 120, such lineage plasticity may also facilitate the adaptation of tumor cells to changing environments during metastasis.…”

Differential impact of RB status on E2F1 reprogramming in human cancer

“…Importantly, higher stringency used to define differentially expressed genes in the model systems used herein identified stronger concordance between in vitro expression data and gene expression profiles from patient tumor samples, further highlighting the clinical relevance of the targets identified in these models. It is of note that the current study used models of AR-positive disease in addition to non-neuroendocrine CRPC tumor samples (SU2C/PCF), as recent studies suggest that RB loss may yield distinct effects in tumors acquiring neuroendocrine phenotypes via RB loss (39,87). Further, as RB loss of expression has been shown in the current study to elicit molecular effects distinct from those driven by phosphorylation-induced inactivation, it is likely that this RB loss-induced gene signature (E2F1 expanded signature) could be applied to other disease types to indicate similar E2F1 reprogramming.…”

The Path of Most Resistance: Transdifferentiation Underlies Exceptional Nonresponses to Androgen Receptor Pathway Inhibition in Prostate Cancer

“…Recent studies have begun to shed light on key drivers of neuroendocrine differentiation that include the involvement of developmental transcription factors such as SOX2 that serve to influence self-renewal and pluripotency, and epigenetic modifiers such as EZH2 that influence embryonic development and cell proliferation (6,7). In this context, Zou and colleagues found that Sox11, a member of the SOXC subclass of HMG-box transcriptional regulators, was upregulated in treatment-resistant NPp53 tumors.…”