SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer

By P. Mu, Zeda Zhang, M. Benelli, W. Karthaus, Elizabeth A. Hoover, Chi-Chao Chen, John Wongvipat, Sheng-Yu Ku, D. Gao, Z. Cao and 14 more. Science, 2017

945 citations recorded by the source corpus.

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. Some cancers evade targeted therapies through a mechanism known as lineage plasticity, whereby tumor cells acquire phenotypic characteristics of a cell lineage whose survival no longer depends on the drug target. We use in vitro and in vivo human prostate cancer models to show that these tumors can develop resistance to the antiandrogen drug enzalutamide by a phenotypic shift from androgen receptor (AR)–dependent luminal epithelial cells to AR-independent basal-like cells. This lineage plasticity is enabled by the loss of TP53 and RB1 function, is mediated by increased expression of the reprogramming transcription factor SOX2, and can be reversed by restoring TP53 and RB1 function or by inhibiting SOX2 expression. Thus, mutations in tumor suppressor genes can create a state of increased cellular plasticity that, when challenged with antiandrogen therapy, promotes resistance through lineage switching.

Subfields: Cancer Research, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/d865462bef2e4e8303b3841e40618f41ada619d2

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Citations in the corpus

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).”
Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling (2017, background): “Notably, repressing AR activity in PacMet-UT1 cells did not result in an NEPC phenotype, and the expression of SOX2, a reprogramming factor associated with transdifferentiation to NEPC, was decreased (Figure 5C) (Mu et al., 2017).”
Overcoming Endocrine Resistance in Breast Cancer (2020, neutral): “Lineage plasticity can also promote antiandrogen resistance and AR-independent growth in a similar fashion to the luminal-tobasal transition mediated by ARID1A inactivation in endocrine-resistant breast cancers (Mu et al., 2017; Xu et al., 2020).”
Hallmarks of Cancer: New Dimensions. (2022, background): “In addition to loss of RB and p53, the acquired resistance to antiandrogen therapy requires upregulated expression of the SOX2 developmental regulatory gene, which is demonstrably instrumental in inducing transdifferentiation of the therapy-responsive adenocarcinoma cells into derivatives that resid”
Genetics and biology of prostate cancer (2018, background): “…that loss of RB1 and TP53 drives lineage plasticity, manifesting as a phenotypic shift from AR-dependent luminal epithelial cells to AR-independent neuroendocrine-like cells—a process driven by activation of the epigenetic reprogramming factors EZH2 and SOX2 (Ku et al. 2017; Mu et al. 2017).”