Breast Cancer Treatment: To tARget or Not? That Is the Question

Abstract

To assess AR's role in TNBC treatment, various existing and completed clinical trials targeting AR or co-targeting AR with other pertinent signaling molecules were analyzed. Cyclin-dependent kinase 4/6 (CDK4/6), cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17 lyase), and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway were some of the most prevalent biomarkers used in combination therapy with AR inhibitors in these trials. Studying how AR functions in tandem with these molecules can have increasing breakthroughs in the treatment options for TNBC. Previous studies have been largely unsuccessful in utilizing AR as the sole drug target for systemic targeted treatment in TNBC. However, there is a lack of other commonly used drug target biomarkers in the treatment of this disease, as well. Thus, analyzing the clinical benefit rate (CBR) within clinical trials that use combination therapy can prove to be imperative to the progression of improving treatment options and prognoses.

Keywords: AR; CDK4/6; CYP17 lyase; DHT; ER; HER2; PI3K/AKT; PR; TNBC.

Figure 1

AR is inactive until DHT binds it, allowing for activation via homodimerization. This homodimer binds to androgen response elements (AREs) to contribute to effects on cell cycle, DNA damage repair, and metastasis. The binding action of AR inhibitors, enzalutamide or bicalutamide, blocks the homodimerization of the receptor and its downstream effects. CYP17 lyase inhibitors such as seviteronel, galeterone, or orteronel can augment the effect of AR inhibitors by blocking the CYP17 lyase pathway, which is imperative to forming the DHT that binds and activates AR. PI3K inhibitors can also block expected downstream effects of AR. These inhibitors include alpelisib, taselisib, and ipatasertib. They bind the receptor upstream of the PI3K-AKT-mTOR pathway, which is involved in regulating the growth and proliferation of the cell. CDK4/6 inhibitors such as palbociclib, abemaciclib, and ribociclib block CDK4/6, the kinase responsible for phosphorylating Retinoblastoma (Rb) tumor suppressor gene, which regulates the cell cycle. When this kinase is inhibited, cell cycle regulation is altered, specifically, the checkpoint between the G1 and S phase, amplifying the effects of AR inhibitors on the cell cycle. Trastuzumab deruxtecan inhibits the HER2 receptor, which diminishes its normal impact on DNA damage repair.