Molecular Pathways: Targeting Steroid Receptor Coactivators in Cancer

Abstract

Coactivators represent a large class of proteins that partner with nuclear receptors and other transcription factors to regulate gene expression. Given their pleiotropic roles in the control of transcription, coactivators have been implicated in a broad range of human disease states, including cancer. This is best typified by the three members of the steroid receptor coactivator (SRC) family, each of which integrates steroid hormone signaling and growth factor pathways to drive oncogenic gene expression programs in breast, endometrial, ovarian, prostate, and other cancers. Because of this, coactivators represent emerging targets for cancer therapeutics, and efforts are now being made to develop SRC-targeting agents, such as the SI-2 inhibitor and the novel SRC stimulator, MCB-613, that are able to block cancer growth in cell culture and animal model systems. Here, we will discuss the mechanisms through which coactivators drive cancer progression and how targeting coactivators represent a novel conceptual approach to combat tumor growth that is distinct from the use of other targeted therapeutic agents. We also will describe efforts to develop next-generation SRC inhibitors and stimulators that can be taken into the clinic for the treatment of recurrent, drug-resistant cancers. Clin Cancer Res; 22(22); 5403-7. ©2016 AACR.

Figure 1

Steroid Receptor Coactivator (SRC) based drugs are predicted to block cancer cell resistance to chemotherapy. SRCs bind to DNA-bound transcription factors (TF) and subsequently recruit co-coactivators such as p300/CBP and CARM1, forming a coactivator complex that drives transcription. In (A), chemotherapeutic agents designed to target ERα such as selective estrogen receptor modulators (SERMS) and degraders (SERDs), HER2 (herceptin and lapitanib), or PI3K (buparlisib) can not block coactivator stimulation of other growth promoting pathways driven through E2F1 or NF-κB in SRC-3-overexpressing cancer cells. (B) In contrast, a SRC targeting SMI is predicted to simultaneously inhibit constitutively active ERα mutants that arise in endocrine-therapy resistant breast cancers and different growth pathways that are concomitantly activated when SRCs are overexpressed, blocking their ability to access alternative growth pathways that become active in endocrine therapy- or chemotherapy-resistant cancer cells.