Targeting Transcription Factors in Cancer

Abstract

Transcription factors (TFs) are commonly deregulated in the pathogenesis of human cancer and are a major class of cancer cell dependencies. Consequently, targeting of TFs can be highly effective in treating particular malignancies, as highlighted by the clinical efficacy of agents that target nuclear hormone receptors. In this review we discuss recent advances in our understanding of TFs as drug targets in oncology, with an emphasis on the emerging chemical approaches to modulate TF function. The remarkable diversity and potency of TFs as drivers of cell transformation justifies a continued pursuit of TFs as therapeutic targets for drug discovery.

Figure 1

Targeting of PML–RARA in Acute Promyelocytic Leukemia. The PML–RARA fusion protein binds to RARA sites in the genome, recruiting co-repressors and repressing RAR-target genes. All-trans retinoic acid (ATRA, labeled as R) binds to PML–RARA and switches it from a repressor of myeloid differentiation genes to an activator. ATRA also induces degradation of PML–RARA through a direct effect on the PIN1 prolyl isomerase. Arsenic trioxide also binds directly to the fusion protein and induces its degradation interacting with the zinc finger of the PML moiety. Arsenic leads to ROS production and subsequent disulfide crosslinking of the cysteines, resulting in oligomerization, SUMOylation, and subsequent ubiquitin-mediated proteolysis. Abbreviations: PIN1, peptidylprolyl cis/trans isomerase 1; PML, promyelocytic leukemia; RARA, retinoic acid receptor α; ROS, reactive oxygen species; SUMO, small ubiquitin-related modifier.

Figure 2

Targeting of CBFβ–SMMHC in inv(16) AML. CBFβ is a cofactor for the TF RUNX1, which together regulate normal hematopoiesis. The inv(16) lesion that defines a subtype of AML results in the joining of smooth-muscle myosin heavy chain to CBFβ. This fusion product is oligomeric and outcompetes wild-type CBFβ for RUNX1 binding. AI-10-49 is a bivalent inhibitor of CBFβ-SMMHC that prevents its interaction with RUNX1, thus restoring the formation of RUNX1–CBFβ heterodimers. Abbreviations: AML, acute myeloid leukemia; CBFβ, core-binding factor, β subunit, RUNX, Runt-related transcription factor; SMMHC, myosin heavy chain 11, smooth muscle.

Figure 3

Targeting the Glucocorticoid Receptor (GR) in Lymphoid Cancers. Endogenous glucocorticoids (G) or synthetic glucocorticoids such as dexamethasone and prednisolone enter a leukemia cell and bind to the GR. Upon binding its ligand, GR is released from heat shock protein (HSP) chaperones, dimerizes, and enters the nucleus. Its key target genes for cancer therapy include the proapoptotic gene BIM (BCL2 interacting mediator of cell death). GR binds to a regulatory element in an intron of BIM, and recruits coactivators to drive expression of BIM to promote apoptosis of normal and neoplastic lymphoid cells. AKT, protein kinase B.

Figure 4

Targeting the Estrogen and Androgen Receptors in Breast and Prostate Cancers, Respectively. (A) Estrogens (E), primarily produced in the ovaries, enter a breast epithelial cell and bind to the estrogen receptor (ER). Upon binding its ligand, ER is released from heat shock protein (HSP) chaperones, dimerizes, and enters the nucleus. Here, it binds to estrogen response elements and recruits coactivators to regulate its target genes to promote the growth, proliferation, and survival of breast cells. Anti-estrogen therapy comes in two major modes: inhibitors of estrogen synthesis, such as the aromatase inhibitors exemestane and letrozole, and inhibitors of ER ligand binding, such as tamoxifen and fulvestrant. (B) Androgens (A) enter a prostate epithelial cell, are converted from testosterone to dihydrotestosterone, and bind to the androgen receptor (AR). Upon binding its ligand, AR is released from HSP chaperones, dimerizes, and enters the nucleus. It recruits coactivator proteins to androgen response elements in the genome, including those regulating the prostate cancer biomarker prostate-specific antigen (PSA), and promotes the growth, proliferation, and survival of prostate cells. Anti-androgen therapy falls principally into two categories: androgen synthesis inhibitors, such as the CYP17A1 inhibitor abiraterone, and inhibitors of ligand binding, such as bicalutamide and enzalutamide.

Figure 5

Targeting Ikaros TFs with Phthalimide Induces Cereblon-Mediated Proteolysis. IKZF1 and IKZF3 are TFs that regulate B cell lineage transcriptional programs. Targets of IKZF1/3 in multiple myeloma include IRF4. Cereblon (CRBN) is an E3 ubiquitin ligase in a complex. Thalidomide and its derivatives pomalidomide and lenalidomide bind to cereblon, blocking its access to its normal ubiquitylation targets. These drugs additionally bind to IKZF1/3, thus recruiting them to the CRBN complex and resulting in their ubiquitylation (U) and proteasomal degradation as a neosubstrate. IKZF, Ikaros family zinc finger 1; IRF4 interferon regulatory factor 4.