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Cellular Origin of Androgen Receptor Pathway-Independent Prostate Cancer and Implications for Therapy

2017; Cell Press; Volume: 32; Issue: 4 Linguagem: Inglês

10.1016/j.ccell.2017.09.011

1878-3686

W. Nathaniel Brennen, John T. Isaacs,

Cancer, Lipids, and Metabolism

In this issue of Cancer Cell, Bluemn et al. report that ∼20% of metastatic castration-resistant prostate cancers express neither AR nor neuroendocrine genes and show AR pathway-independent growth, driven instead by a FGFR/MAPK/ID1 signaling cascade. These results provide a strong rationale for co-targeting AR bypass pathways with initial AR antagonism. In this issue of Cancer Cell, Bluemn et al. report that ∼20% of metastatic castration-resistant prostate cancers express neither AR nor neuroendocrine genes and show AR pathway-independent growth, driven instead by a FGFR/MAPK/ID1 signaling cascade. These results provide a strong rationale for co-targeting AR bypass pathways with initial AR antagonism. The majority of metastatic prostate cancers (PCs) progress during conventional LHRH analog androgen deprivation therapy (ADT) but remain AR pathway active (ARPC), as demonstrated by expression of AR and AR-regulated genes like PSA. Bluemn et al. report in this issue of Cancer Cell that chronic ADT combined sequentially with androgen receptor (AR) pathway antagonists like abiraterone and enzalutamide is associated with a 4-fold increase in the proportion of metastatic castration-resistant prostate cancers (mCRPCs) that are AR and neuroendocrine (NE) negative (i.e., "double-negative" PC [DNPC]), such that ∼20% of mCRPC patients now present as this DNPC phenotype (Bluemn et al., 2017Bluemn E.G. Coleman I.M. Lucas J.M. Coleman R.T. Hernandez-Lopez S. Tharakan R. Bianchi-Frias D. Dumpit R.F. Kaipainen A. Corella A.N. et al.Cancer Cell. 2017; 32 (this issue): 474-489Scopus (331) Google Scholar). The authors document that, similar to ARPCs, these DNPCs retain common genetic alterations like TP53 mutations, PTEN loss, and AR amplification, indicating that recurrent genomic alterations do not explain the marked phenotypic differences between ARPC and DNPC. In addition, using a series of molecular, cell, and tumor biology approaches, Bluemn et al. report that DNPC growth is driven by acquisition of fibroblast growth factor receptor (FGFR)/mitogen-activated protein kinase (MAPK)/Inhibitor of Differentiation 1 (ID1) signaling the autocrine/paracrine pathway and are thus sensitive to small-molecule inhibitors of the FGFR and MAPK signaling cascade in preclinical models. This conclusion is consistent with an early clinical observation of a 26% response rate in men with mCRPC unselected for loss of AR, and thus not enriched in DNPCs, when treated with a multi-targeted receptor tyrosine kinase inhibitor against FGFR, FLT3, KIT, VEGFR, PDGFRα, and PDGFRβ (Wan et al., 2014Wan X. Corn P.G. Yang J. Palanisamy N. Starbuck M.W. Efstathiou E. Li Ning Tapia E.M. Zurita A.J. Aparicio A. Ravoori M.K. et al.Sci. Transl. Med. 2014; 6: 252ra122Crossref PubMed Scopus (75) Google Scholar). The results of Bluemn et al. provide a strong rationale for clinical trials with more-specific FGFR and/or MAPK inhibitors, particularly in mCRPC patients stratified by AR activity to enrich for DNPCs. These studies also resurface the long-standing unresolved question as to the origin of the initially transformed prostate epithelial cell, and to what the mechanism is for their progression to the ARPC versus NEPC versus DNPC subtypes of mCRPC. More than 30 years ago, it was demonstrated that normal prostate can undergo successive cycles of androgen deprivation and replacement without diminishing its ability for continued epithelial regeneration (Isaacs, 1999Isaacs J.T. Urol. Clin. North Am. 1999; 26: 263-273Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar). Since then, a large number of independent groups have clarified how the human prostate epithelium is organized into adult prostate epithelial stem cell units and how this organization allows such profound cyclic regenerative growth capacity (Isaacs, 1999Isaacs J.T. Urol. Clin. North Am. 1999; 26: 263-273Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar, Moad et al., 2017Moad M. Hannezo E. Buczacki S.J. Wilson L. El-Sherif A. Sims D. Pickard R. Wright N.A. Williamson S.C. Turnbull D.M. et al.Cell Rep. 2017; 20: 1609-1622Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). In these human adult prostate epithelial stem units, AR-negative adult prostate epithelial stem cells are located in the basal layer of the epithelium in niches that control their survival and self-renewal (Moad et al., 2017Moad M. Hannezo E. Buczacki S.J. Wilson L. El-Sherif A. Sims D. Pickard R. Wright N.A. Williamson S.C. Turnbull D.M. et al.Cell Rep. 2017; 20: 1609-1622Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). The androgen independence of the adult prostate epithelial stem cells is supported by the tissue recombination studies of Gerry Cunha, who documented that epithelial morphogenesis occurs even when AR protein is not expressed by any prostate epithelial cells, including stem cells, as long as there is ligand-dependent AR paracrine signaling in the supporting stromal cells (Isaacs, 1999Isaacs J.T. Urol. Clin. North Am. 1999; 26: 263-273Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar, Litvinov et al., 2003Litvinov I.V. De Marzo A.M. Isaacs J.T. J. Clin. Endocrinol. Metab. 2003; 88: 2972-2982Crossref PubMed Scopus (179) Google Scholar). The mechanism for epithelial morphogenesis without AR expression in the epithelial cells is related to the hierarchical expansion and maturation of adult AR-negative prostate epithelial stem cells and their progeny (Figure 1). Adult AR-negative prostate epithelial stem cells in the basal epithelial layer undergo self-renewal division in which one daughter cell remains a stem cell and the other daughter cell occasionally differentiates into a non-proliferating, AR-negative neuroendocrine cell (NE), with the much more prevalent pathway being differentiated into a ΔNp63-positive/AR-negative transient amplifying (TA) progenitor cell. TA progenitor cells undergo a limited number of amplifying rounds of proliferation before maturing into ΔNp63-negative intermediate cells. Such TA proliferation requires the androgen-regulated production and secretion of diffusible stromal-derived paracrine peptide growth factors collectively termed "andromedins" (Isaacs, 1999Isaacs J.T. Urol. Clin. North Am. 1999; 26: 263-273Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar, Litvinov et al., 2003Litvinov I.V. De Marzo A.M. Isaacs J.T. J. Clin. Endocrinol. Metab. 2003; 88: 2972-2982Crossref PubMed Scopus (179) Google Scholar). These paracrine-secreted andromedins diffuse from the stroma into the epithelial compartment, where their binding to cognate receptors stimulates TA cell proliferation and maturation into intermediate cells. These intermediate cells begin to express an increasing level of AR protein as they migrate from the basal to the luminal layer, where androgen-dependent andromedin-driven growth stimulation is counter-balanced by androgen-induced AR binding to nuclear β-catenin/TCF-4 complexes that inhibit c-Myc transcription, which results in their terminal G0 growth arrest. This cell-autonomous ligand-induced AR-driven growth arrest is coupled with AR binding to response elements in the enhancer/promoter of AR target genes like PSA, thereby inducing terminal differentiation into ΔNp63-negative, PSA-expressing secretory luminal cells (Antony et al., 2014Antony L. van der Schoor F. Dalrymple S.L. Isaacs J.T. Prostate. 2014; 74: 1118-1131Crossref PubMed Scopus (49) Google Scholar). Based on this stem cell hierarchical organization, prostatic carcinogenesis has multiple possible origins, because potentially any of the cell types in the hierarchy could undergo malignant transformation to produce a cancer-initiating cell (CIC). Furthermore, the specific cell of origin for the CICs makes a seminally important determinate as to whether ADT can be curative for metastatic PC. If the CIC is derived from an AR-negative NE cell, stem cell, or TA cell, this would explain why conventional ADT, even when combined with abiraterone and/or enzalutamide, is so rarely curative for metastatic PC. This is because such combined therapy does not eliminate the CICs even though the hierarchical clonal expansion of these CICs produces a heterogeneous population, with the majority of the cancer cells expressing AR and eliminated by ADT. Alternatively, major hardwiring changes in the androgen receptor signaling pathways can occur in AR-expressing intermediate or secretory luminal cells such that ligand-dependent AR binding in the nuclei of malignant cells no longer suppresses continuous growth via c-Myc suppression. In contrast, in such cells, androgen-induced AR signaling paradoxically upregulates c-Myc expression and stimulates growth, thus converting AR signaling from a growth suppressor in normal prostate epithelial cells to an autocrine oncogene in these intermediate or secretory luminal-derived CICs. Indeed, loss of AR-dependent growth suppression can occur even in hormonally naive localized PC cells in which oncogenic gain has not occurred (D'Antonio et al., 2010D'Antonio J.M. Vander Griend D.J. Antony L. Ndikuyeze G. Dalrymple S.L. Koochekpour S. Isaacs J.T. PLoS One. 2010; 5: e11475Crossref PubMed Scopus (29) Google Scholar). Even if the CIC is initially derived from malignant transformation of such AR-positive cells, AR-negative NE single-positive (AR-/NE+ PC) and/or DNPC malignant progeny can develop stochastically in the presence of physiologic androgen due to genetic instability or via adaptive pressure during ADT (Ku et al., 2017Ku S.Y. Rosario S. Wang Y. Mu P. Seshadri M. Goodrich Z.W. Goodrich M.M. Labbé D.P. Gomez E.C. Wang J. et al.Science. 2017; 355: 78-83Crossref PubMed Scopus (563) Google Scholar). Thus, once developed, such AR pathway-independent populations are not eliminated by ADT, no matter how complete. This realization provides strong support for the conclusion of the Bluemn et al. study that co-targeting AR bypass pathways, like the FGF/FGFR/MAPK/ID1 cascade that Bluemn et al. discovered, should be combined as early as possible with complete AR antagonism. Such combinatorial chemohormonal approaches that simultaneously co-target AR-positive and AR pathway-independent PC cell populations within heterogeneous tumors were proposed nearly 30 years ago based on preclinical animal models (Isaacs, 1989Isaacs J.T. Cancer Res. 1989; 49: 6290-6294PubMed Google Scholar), which have been validated by a recent clinical trial (Sweeney et al., 2015Sweeney C.J. Chen Y.H. Carducci M. Liu G. Jarrard D.F. Eisenberger M. Wong Y.N. Hahn N. Kohli M. Cooney M.M. et al.N. Engl. J. Med. 2015; 373: 737-746Crossref PubMed Scopus (1777) Google Scholar). Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF SignalingBluemn et al.Cancer CellOctober 09, 2017In BriefBluemn et al. show that androgen receptor (AR) inhibition results in a phenotypic shift in castration-resistant prostate cancer, leading to tumors that are AR-null but not neuroendocrine (NE). Models for AR-null, non-NE tumors show elevated FGF and MAPK activity and are sensitive to blockade of these pathways. Full-Text PDF Open Archive