Novel proteolysis-targeting chimera targeting RAD51 for the treatment of triple-negative breast cancer.

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive subtype characterized by the absence of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2. RAD51 is associated with homologous recombination repair (HRR), a crucial DNA repair mechanism. This paper reports the development and efficacy of a novel targeted RAD51 degrader compound, TRD2, for treating TNBC. TRD2 is synthesized by linking a RAD51 binder to the ligand of the E3 ligase cereblon (CRBN). The results showed that TRD2 effectively reduces the RAD51 protein levels in TNBC cells and exhibits potent anticancer effects in vitro and in vivo. Mechanistic studies showed that TRD2 induces RAD51 ubiquitination and subsequent proteasomal degradation by binding to CRBN. Furthermore, TRD2 demonstrated significant tumor growth inhibition in a mouse xenograft model of TNBC. These findings highlight the potential of TRD2 as a promising therapeutic approach in TNBC, leveraging Proteolysis-targeting chimera (PROTAC) technology to degrade the overexpressed RAD51 protein selectively. The study emphasizes the importance of targeting DNA damage repair core proteins and suggests that TRD2 could overcome challenges posed by resistance to conventional therapies. Nevertheless, additional experiments will be needed to validate these observations and explore the potential impacts on other proteins and cancer types. Overall, this research introduces a novel strategy for TNBC treatment, addressing the limitations of current therapeutic options.