Targeting Steroid Receptor Coactivators in Cancer David M

Published OnlineFirst September 21, 2016; DOI: 10.1158/1078-0432.CCR-15-1958

Molecular Pathways Clinical Cancer Research Molecular Pathways: Targeting Steroid Receptor Coactivators in Cancer David M. Lonard and Bert W. O'Malley

Abstract

Coactivators represent a large class of proteins that partner made to develop SRC-targeting agents, such as the SI-2 inhib- with nuclear receptors and other transcription factors to regu- itor and the novel SRC stimulator, MCB-613, that are able to late gene expression. Given their pleiotropic roles in the control block cancer growth in cell culture and animal model systems. of transcription, coactivators have been implicated in a broad Here, we will discuss the mechanisms through which coacti- range of human disease states, including cancer. This is best vators drive cancer progression and how targeting coactivators typiﬁed by the three members of the steroid receptor coacti- represent a novel conceptual approach to combat tumor growth vator (SRC) family, each of which integrates steroid hormone that is distinct from the use of other targeted therapeutic agents. signaling and growth factor pathways to drive oncogenic gene We also will describe efforts to develop next-generation SRC expression programs in breast, endometrial, ovarian, prostate, inhibitors and stimulators that can be taken into the clinic for and other cancers. Because of this, coactivators represent emerg- the treatment of recurrent, drug-resistant cancers. Clin Cancer Res; ing targets for cancer therapeutics, and efforts are now being 22(22); 1–5. 2016 AACR.

Background SRCs in addition to histones, altering SRC activity and protein stability (6). In addition to SRCs, these SRC-associated co- The nuclear receptors (NR) gene superfamily consists of ligand- coactivators provide an entree for therapeutic interventions activated transcription factors that respond to steroid and other with small-molecule inhibitors (SMI), such as the p300 HAT lipophilic hormones, or that in some cases are "orphan" receptors inhibitor C646 (7). for which no ligand exists or has been identified to date (1). NRs regulate a diverse array of physiologic processes and, as a conse- quence, are often coopted by cancer cells to drive tumor growth. SRCs in breast cancer However, a large body of research has reinforced the notion that Because of their strong connection with NRs, SRC proteins NRs cannot drive transcription by themselves and rely on coacti- have been recognized as key oncoproteins in hormone-depen- vators to act as key intermediaries needed to modify and interpret dent cancers. For instance, elevated SRC expression and activity the epigenome and signaling functions as essential enablers for is a driving force in the initiation and progression of ERa- NR-mediated transcription. positive breast cancers. The SRC-3 gene is amplified in 5% to At this time, more than 400 coactivators have been reported in 10% of breast cancers (8, 9), and the SRC-3 mRNA or protein the literature (2). The first identified coactivator, steroid receptor has been found to be overexpressed by approximately 60% in coactivator 1 (NCOA1/SRC-1), was characterized as a protein that different breast cancer patient cohorts (8, 10, 11). SRC-3 over- can stimulate the transcriptional activities of the progesterone expression was found to be associated with more aggressive receptor, the estrogen receptor a (ESR1/ERa), and other NRs (3). breast cancers (9, 12) and poor survival rates (13). Consistent Two other members of the SRC family, SRC-2 (NCOA2/TIF2/ with this, clinical data from breast cancer patients indicate that GRIP1) and SRC-3 (NCOA3/AIB1/RAC3/ACTR/pCIP), were sub- high SRC-3 expression is associated with decreased disease-free sequently identified (4), and SRCs have been substantiated as the survival (14). In genetically engineered MMTV-v-ras and primary platform coactivators that serve as scaffolds for building a MMTV-Erbb2 mouse models, loss of SRC-3 reduces breast multi-protein coactivator protein complex containing co-coacti- tumor incidence and delays tumor growth and development vator chromatin-modifying enzymes, including CREB-binding (15, 16). In both models, insulin-like growth factor 1 (IGF1) protein (CREBBP/CBP), p300 (EP300), coactivator-associated and ERBB2 signaling pathways are impaired in the absence of arginine methyltransferase 1 (CARM1), and other proteins (5). SRC-3, implicating that kinase signaling cascades independent In many cases, these co-coactivators posttranslationally modify of ERa are also involved in coactivator-dependent breast cancer tumor progression. Expanding on this idea that SRCs can drive multiple cancer growth signaling systems, SRC-3 has been Department of Molecular and Cellular Biology, Baylor College of shown to coactivate other transcription factors, such as the Ets Medicine, Houston, Texas. transcription factor polyoma enhancer activator 3 (PEA3), Corresponding Author: Bert W. O'Malley, Department of Molecular and Cellular leading to increased expression of matrix metalloproteinase Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. 2 (MMP2) and MMP9, leading to metastasis (17). Phone: 713-798-6205; Fax: 713-798-5599; E-mail: [email protected] The multifunctional role for SRC-3 as a broad integrator of doi: 10.1158/1078-0432.CCR-15-1958 additional cancer cell growth programs is further reinforced by the 2016 American Association for Cancer Research. finding that a splice variant of SRC-3 (SRC-3D4) functions as a

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Escape pathways not Steroid receptor coactivator (SRC)- inhibited by current targeted targeting agents simultaneously block therapeutic agents multiple cancer growth pathways Figure 1. SRC-based drugs are predicted to block cancer cell resistance to Targeted therapies SRC SMI Buparlisib chemotherapy. SRCs bind to DNA- bound transcription factors (TF) and CBP/p300 CARM1 SERMs, SERDs subsequently recruit co-coactivators, Herceptin CBP/p300 CARM1 lapatinib SRCs such as p300/CBP and CARM1, forming SRCs a coactivator complex that drives TF TF TF TF transcription. A, chemotherapeutic agents designed to target ERa,suchas selective ER modulators (SERMS) and degraders (SERD), HER2 (Herceptin and lapatinib), or PI3K (buparlisib) cannot block coactivator stimulation of HER2/ PI3K/ ERα or ERα HER2/ PI3K/ other growth-promoting pathways ERα E2F1 NF-κB E2F1 NF-κB neu AKT mutants neu AKT driven through E2F1 or NF-kBin SRC-3–overexpressing cancer cells. B, in contrast, an SRC-targeting SMI is predicted to simultaneously inhibit constitutively active ERa mutants that arise in endocrine therapy–resistant Cancer cell Cancer cell breast cancers and different growth pathways that are concomitantly activated when SRCs are overexpressed, blocking their ability to Cancer cell evades growth Cancer cell cannot evade SRC access alternative growth pathways inhibition by exploiting SMI that broadly disrupts that become active in endocrine alternative growth pathways multiple growth pathways therapy or chemotherapy-resistant cancer cells.

bridging adaptor between the EGFR and focal adhesion kinase target the transcriptional function of these gain-of-function (FAK), potentiating cancer cell migration and invasion in a non- mutant ERa proteins (Fig. 1). genomic manner (18). SRCs in prostate, endometrial, and ovarian cancer Role of SRCs in endocrine therapy–resistant breast cancers A comprehensive sequencing analysis of human prostate SRC-3 has been implicated in clinical resistance to tamoxifen tumors found that 8% of primary and 37% of metastatic tumors and aromatase inhibitors, and this has been traditionally attrib- either have amplifications of the SRC-2 gene or overexpress its uted to the role that SRC-3 has in stimulating growth factor mRNA (24). Primary prostate tumors with SRC-2 gain of function signaling pathways, circumventing the inhibition of ERa in breast have elevated androgen receptor (AR) signaling, consistent with cancer cells (19, 20), consistent with the pleiotropic actions that the known role of SRC-2 as an AR coactivator. These findings are we have described for SRC-3 above. Recent studies that have in agreement with earlier studies that showed a correlation sought to uncover genomic alterations that underlie endocrine between SRC-2 expression and high tumor grade and poor therapy resistance have provided additional layer of detail point- survival (25–27). Interestingly, SRC-2 has been shown to be a ing to a role for SRC-3 in recurrent breast cancer. Sequencing of key regulator of energy homeostasis (28–31), and this fact has tumors from breast cancer patients that have acquired resistance been linked to its role as a regulator of prostate cancer metabolic to aromatase inhibitors has revealed the presence of recurrent programming. Specifically, SRC-2 drives glutamine-dependent mutations in the ligand-binding domain of the ERa gene, result- and sterol-regulatory element–binding protein 1 (SREBP1)– ing in activation of the receptor in the absence of estrogens (21). mediated de novo lipogenesis that enhances prostate cancer cell These mutant receptors also are refractory to the pure antiestrogen survival and metastasis (32). SRC-3 and SRC-1 have also been fulvestrant, and considerable effort has been directed toward the reported to be overexpressed in prostate cancers, and their expres- development of next-generation, orally available selective estro- sion levels have been positively correlated with tumor grade and gen degraders (SERD) to target these mutant ERa proteins (22). disease recurrence (33). Importantly, these mutant ERa proteins interact with SRCs in the As coactivators for ERa, SRCs have been implicated in other absence of estrogens, pointing to a vital role for SRCs in driving estrogen-related cancers, such as endometrial and ovarian cancer. hormone therapy–refractory breast cancers that harbor ESR1 mRNA levels of all three SRCs are significantly increased in mutations (23). We speculate that in addition to the development endometrial carcinoma (34), and SRC-3 expression is correlated of newer and more potent SERDs, SRC SMIs may prove to be with clinical stage, depth of myometrial invasion, differentiation, powerful agents when used in combination with SERDs to better and poor prognosis (35, 36). Earlier on, SRC-3 was found to be

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amplified in ovarian cancer (8, 9), and elevated SRC-3 expression bufalin, was developed to overcome the solubility problem of has been found in 64% of high-grade ovarian cancers, and its bufalin, and it was proved to be equally efficient in inhibiting levels are correlated with tumor progression (37). SRCs have also tumor growth in an orthotopic breast cancer model (55). Impor- been implicated in a wide variety of cancers, including pancreatic tantly, additional investigations of compounds identified from (38, 39), colon (40), lung (41), and other cancers (2). this high-throughput screen led to the identification and medic- inal chemistry development of additional compounds with stron- Clinical–Translational Advances ger drug-like properties, such as SI-2 (56). SI-2 is able to selectively kill cancer cells at low nanomolar ranges (3–20 nmol/L) and can As coactivators for NRs, SRCs are essential components of inhibit primary tumor growth in a triple-negative breast cancer steroid hormone signaling, providing a strong impetus to develop xenograft tumor model. Pharmacologic parameters of SI-2 and SRC-targeting agents for the treatment of endocrine-related can- structurally related compounds have been determined, revealing cers. Moreover, as described above, SRCs also function as coacti- that SI-2 is rapidly cleared from the bloodstream in mice. Ongoing vators for other transcription factors, including NF-kB (NFKB1; effort is being made to identify SI-2 derivatives with improved ref. 42), SREBP1 (32), PEA3 (43, 44), and AP-1 (JUN; refs. 45, 46), stability in vivo. making the potential for SRC-targeting drugs pertinent to a wide range of cancers where steroid hormone signaling is not directly SRC small-molecule stimulators: Oncogene hyperstimulation implicated. as a novel paradigm for cancer therapy An important concept related to the oncogenic role for SRCs in Interestingly, the quest for SRC small molecule–targeting cancer revolves around their roles as integrators of growth factor agents has led to an unexpected turn and a novel concept for kinase signaling cascades and growth-promoting transcriptional cancer therapy. High-throughput screening led to the discovery programs utilized by cancer cells. For instance, SRC-3 sits at a of MCB-613, a SRC small-molecule stimulator (SMS; ref. 57). nexus for MAPK, FAK, ABL, and GSK3b (GSK3B) kinase signaling MCB-613 hyperstimulates SRC oncoproteins and can selec- cascades that phosphorylate distinct residues on the SRC-3 pro- tively kill cancer cells and inhibit tumor growth in a breast tein that forms a phosphorylation code that determines its ability cancer xenograft mouse model. MCB-613 increases SRCs' inter- to interact with different classes of transcription factors (47). An action with other coactivators, such as CBP and CARM1, and by important corollary of this fact is in contrast to most targeted strongly hyperstimulating SRC-related growth programs, it therapeutic agents, inhibition of SRC-3 function can simulta- induces proteostasis and reactive oxygen species stress that is neously interfere with multiple growth-related signaling path- well beyond that which cancer cells can cope. Considering the ways and provides promise to deny the cancer's ability to develop oncogenic roles of SRCs, it appears to be counterintuitive to acquired resistance through the activation of alternative escape employ SRC SMS in treating cancer. However, in comparison pathways (Fig. 1). with normal cells, cancer cells are already under high levels of stress from increased protein synthesis/folding and metabolism Development of SRC-targeting agents due to their highly proliferative nature. It is of the utmost Because SRCs lack a high-affinity ligand-binding domain and importance for them to fully engage their stress response path- primarily function as a scaffold for the assembly of co-coactivators ways to maintain homeostasis, making them more vulnerable through protein–protein interactions, SRCs have been considered than normal cells to stressors, such as MCB-613. By acutely difficult drug targets. However, given their key roles as prominent overstimulating SRC family proteins, MCB-613 overloads the oncoproteins, this challenge is outweighed by the potential ther- stress response system of cancer cells and selectively kills them. apeutic benefit that SRC-targeting drugs may bring. Earlier on, Thus, targeting the SRC coactivators, either by inhibition or several groups performed compound screening campaigns to stimulation, represents novel and promising approaches for develop agents to disrupt the binding of SRCs to NRs, such as cancer therapeutic development. The identification of MCB- ERa,ERb (ESR2), and peroxisome proliferator–activated receptor 613 not only points to additional ways to target SRCs but g (PPARG; refs. 48–50); however, these screens specifically suggests that strategies that seek to stimulate other oncogenes focused on targeting the NR-coactivator protein–protein inter- represent an unexploited space for future drug development face. Some additional efforts have been made to identify and that might bear fruit as well. develop additional disruptors of SRC-NR binding, and some structure–activity relationship information has been obtained for these molecules (51). However, additional work is needed to Conclusions identify compounds with greater potency, and none of these are Coactivators are necessary for NRs and other transcription currently ready to take into the clinic. factors to drive target gene expression and as such, are fre- In contrast, our laboratory has focused on targeting SRC pro- quently exploited by cancer cells to drive proliferation, inva- teins directly, and we identified gossypol as a proof-of-concept sion, and other oncogenic programs. By integrating and pro- SMI for SRC-1 and SRC-3, for the first time establishing that SRC moting growth signaling pathways used by cancer cells, SRCs proteins can be directly targeted by small-molecule compounds represent emerging targets for cancer therapeutics, and SRC- (52). In a subsequent high-throughput screen of a large chemical targeting agents have been identified that show promise as library containing compounds from the large NIH-Molecular potential new cancer therapies. Because SRCs have been found Libraries Probe Production Centers Network, improved SRC SMIs to be overexpressed in such a wide breadth of cancer types, SRC were identified, including bufalin and verrucarin A (53, 54). SMIs and SMSs may ultimately find broad use in the clinic (5). Bufalin promotes the degradation of SRC-3 and SRC-1 in a SRCs represent a novel group of oncoprotein drug targets not proteasome-dependent manner and efficiently blocks cancer cell currently represented in the armamentarium of clinically avail- growth in vitro and in vivo. A water-soluble analogue, 3-phospho able drugs, but ongoing drug development efforts promise to

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address this unmet clinical need. In a conceptual sense, SRCs' Authors' Contributions key roles as growth factor and steroid hormone signaling Conception and design: D.M. Lonard, B.W. O'Malley integrators also make them unique targets for next-generation Writing, review, and/or revision of the manuscript: D.M. Lonard, SRC SMIs that can disrupt communication across these steroid B.W. O'Malley and kinase growth-simulating pathways as well as for SRC SMSs that can kill cancer through coactivator hyperstimulation- Grant Support induced tumor cell stress. This work was supported by funding from the Department of Defense Breast Cancer Research Program (BC120894), the Cancer Prevention and Research Institute of Texas (RP100348 and RP101251), and from the NIH (DK059820, to Disclosure of Potential Conﬂicts of Interest B.W. O'Malley; HD076596, to D.M. Lonard). High-throughput screening was D.M. Lonard reports receiving commercial research support from Coregon, supported through the NIH Molecular Libraries Program. Inc. B.W. O'Malley reports receiving commercial research grants from and has ownership interest (including patents) in Coregon, Inc. No other potential Received August 4, 2016; revised August 24, 2016; accepted September 1, conﬂicts of interest were disclosed. 2016; published OnlineFirst September 21, 2016.

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Molecular Pathways: Targeting Steroid Receptor Coactivators in Cancer

David M. Lonard and Bert W. O'Malley

Clin Cancer Res Published OnlineFirst September 21, 2016.

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