Proteolysis Targeting Chimera (PROTAC) as a promising novel therapeutic modality for the treatment of triple‐negative breast cancer (TNBC)

Abstract

Breast cancer (BC) is considered one of the most prevalent malignancies impacting women worldwide, constituting 15% of all new cancer cases. It is classified according to its molecular targets into three subtypes; HR+/ERBB2‐, ERBB2+/HR+, or HR‐ and triple‐negative breast cancer (TNBC). TNBC is considered aggressive cancer with bad prognosis and poor clinical outcomes. It lacks estrogen, progesterone, and ERBB2 receptors rendering its treatment more challenging. Owing to its unresponsiveness to hormonal therapy, quick tumor growth, and the high probability to have spread at the time of discovery, it is more likely to recur following therapy. Proteolysis Targeting Chimeric molecules (PROTACs) are hetero‐bifunctional molecules that are able to hijack the ubiquitin‐proteasome system, a major physiological proteolytic mechanism. This leads to ubiquitination through endogenous E3 ligases and subsequent degradation through 26‐S proteasome. Since its discovery in 2001, PROTACs have been considered an important therapeutic modality due to their ability to target and degrade undruggable proteins. In vitro studies have been conducted to investigate the possibility of using PROTACs as a therapeutic modality in TNBC. Data available propose great potential of PROTACs technology as a major candidate in TNBC management. Further in vitro and in vivo clinical trials are required to establish a definitive decision. In this review, we aim to give a brief overview of TNBC and PROTACs and highlight the rationale behind using PROTACs as a therapeutic modality in patients with TNBC.

Therapeutic evolution in HR+/HER2- breast cancer: from targeted therapy to endocrine therapy

“…Clinical trials are ongoing in patients with HR+/HER2– advanced breast cancer previously treated with endocrine therapy and CDK4/6 inhibitors. Preliminary results showed that vepdegestrant has good clinical activity and tolerance ( Li et al, 2022 ; Dogheim and Amralla, 2023 ). However, to determine the optimal use of PROTACs and their long-term safety and efficacy in breast cancer, monitoring and tracking of toxicological effects will be required in the later stages of clinical studies and drug development of PROTACs ( Qi et al, 2021 ; Li et al, 2022 ; Dogheim and Amralla, 2023 ).…”

PROTACs: Emerging Targeted Protein Degradation Approaches for Advanced Druggable Strategies

“…In particular, in vitro studies have shown promise for using PROTACs as a therapeutic modality in triple-negative breast cancer (TNBC). Although the data suggests great potential, further research is needed, including in vitro and in vivo clinical trials, to fully establish the safety and efficacy of using PROTACs in TNBC treatment [ 81 ]. PROTACs have emerged as a promising class of therapeutics for lung cancer and drug resistance in recent years.…”

Efficacy of apatinib 250 mg combined with chemotherapy in patients with pretreated advanced breast cancer in a real-world setting

“…There is no evidence suggesting that any chemotherapeutic drugs have superior efficacy in the second and later lines, and new drugs or strategies are required for this population of patients. Some new therapeutic strategies for MBC such as anti-angiogenesis therapy, androgen receptor antagonists, micro-RNA based therapy, proteolysis targeting chimeric molecules (PROTACs) and others are under exploration,some of them have initially shown potential benefits ( 2 , 3 ).…”