Molecular Mechanisms of Anti-Estrogen Therapy Resistance and Novel Targeted Therapies

Abstract

Breast cancer (BC) is the most commonly diagnosed cancer in women, constituting one-third of all cancers in women, and it is the second leading cause of cancer-related deaths in the United States. Anti-estrogen therapies, such as selective estrogen receptor modulators, significantly improve survival in estrogen receptor-positive (ER+) BC patients, which represents about 70% of cases. However, about 60% of patients inevitably experience intrinsic or acquired resistance to anti-estrogen therapies, representing a major clinical problem that leads to relapse, metastasis, and patient deaths. The resistance mechanisms involve mutations of the direct targets of anti-estrogen therapies, compensatory survival pathways, as well as alterations in the expression of non-coding RNAs (e.g., microRNA) that regulate the activity of survival and signaling pathways. Although cyclin-dependent kinase 4/6 and phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitors have significantly improved survival, the efficacy of these therapies alone and in combination with anti-estrogen therapy for advanced ER+ BC, are not curative in advanced and metastatic disease. Therefore, understanding the molecular mechanisms causing treatment resistance is critical for developing highly effective therapies and improving patient survival. This review focuses on the key mechanisms that contribute to anti-estrogen therapy resistance and potential new treatment strategies alone and in combination with anti-estrogen drugs to improve the survival of BC patients.

Non-Coding RNAs Modulating Estrogen Signaling and Response to Endocrine Therapy in Breast Cancer

“…Endocrine resistance can emerge from different key mechanisms [ 9 , 10 ]. It can result from impaired estrogen signaling resulting from downregulation, mutation, aberrant phosphorylation, or altered stability of ERα, from an imbalance between ER coactivator and corepressor proteins or ER-binding transcription factors, and from ligand-independent activation of estrogen receptors [ 11 , 12 , 13 , 14 ].…”

Selenium Analogue of LSZ102 as a Highly Potent ER‐α Binder

“…SERMs are competitive binders of ER, but AIs inhibit the key enzyme responsible for the biosynthesis of estrogen itself [9] . Unfortunately, almost one third of the patients under ET treatment develop resistance to these drugs and consequently they do not respond to the treatment or the disease reoccurs [10] . As the main contributor to the development of ET resistance has been recognized mutation in the ligand binding domain (LBD) of estrogen receptor 1 (ESR1) [11] …”

“…[9] Unfortunately, almost one third of the patients under ET treatment develop resistance to these drugs and consequently they do not respond to the treatment or the disease reoccurs. [10] As the main contributor to the development of ET resistance has been recognized mutation in the ligand binding domain (LBD) of estrogen receptor 1 (ESR1). [11] More recently, an alternative approach for the treatment of ER + BC has been discovered, namely, use of selective estrogen receptor degraders or downregulators (SERDs).…”

“…[12d] Therefore, the development of new orally available SERD or SERM/SERD hybrid (SSH) drugs is actively pursued. [13] Giredestrant or GDC-9545 (7) [14] is probably the best oral SERD to date, but numerous other compounds have shown high potency and have entered clinical trials, including benzo[b]thiophene based rintodestrant or G1T48 (8) and LSZ102 (10). [14b] Wide range of different cyclic systems have served as molecular platforms for the construction of the SERD activity possessing compounds; those include indole, [14,15] indazole, [16] 1,3,5-triazine, [17] 1,2,3,4-tetrahydronaphthalene, [18] 2Hchromene, [3] 8,9-dihydro-7H-benzo [7]annulene, [19] benzo[b]thiophene, [20] and others.…”

Switching from Aromatase Inhibitors to Dual Targeting Flavonoid-Based Compounds for Breast Cancer Treatment

“…Several studies have dealt with the mechanisms involved in the resistance to antiestrogen therapies, primarily focusing on the complex functions and roles of ERα and on the interconnection between the estrogen signaling network and different cellular pathways [ 5 , 6 ]. These mechanisms may depend on ERα mutations, a reduction in ERα expression, increased drug metabolism and/or drug efflux via the multidrug resistance P-glycoprotein, and overexpression of antiestrogen-binding site proteins able of seizing the administered therapeutic [ 7 ]. For these reasons, research is still required for the development of new potential strategies and new compounds to fight BC.…”