Breaking Barriers in Breast Cancer: Multi-Targeted Therapeutic Insights

Breast cancer accounts for one of the leading causes of cancer deaths in women globally. Breast cancer is characterized by molecular heterogeneity, and different patients show various responses to therapy. In addition to hormone therapies, there are targeted agents and immunotherapies, but resistance to therapy and recurrence remain a critical clinical problem for patients.

This review is aimed at presenting innovations in multi-targeted therapies against breast cancer. It also includes an understanding of the biological mechanisms in pathways of this disease in relation to these agents to address treatment failure. The molecular pathways examined are ER, HER2, EGFR, VEGFR, PI3K/AKT/mTOR, MAPK, PARP, and CDK4/6. Additionally, KAT6A is identified as a molecular target along with new clinical agents that are being reviewed, as well as combinations of strategies using molecular profiling and pathology reports.

The major signaling pathways that control breast cancer progression and resistance, and/or sensitivity to therapy. KAT6A, a histone acetylase, was amplified in all of the ER+ breast cancers, suggesting that it can be used as a biomarker for assessing the effectiveness of CDK4/6 inhibitors and is an epigenetic therapeutic target in mammary cell lines. KAT6A is being developed as a selective KAT6 inhibitor; however, it seems most benefits may come from additional inhibitors of Menin, which could help overcome endocrine therapeutic resistance. We also reviewed CDK4/6 Mutations and resistance invariably associated with palbociclib, as well as immunotherapy with antibody- drug conjugate, including trastuzumab deruxtecan (DS-8201).

Multi-pathway targeting holds promise to overcome shortcomings of current monotherapies. Due to the complexity of the breast cancer molecular landscape, we must plan for and potentially target resistance mechanisms. The use of KAT6A as a biomarker, along with the use of novel inhibitors, may help inform treatment decisions and improve outcomes. Additionally, this review has identified the need to position the surveillance and addressing of our resistance mechanisms for current therapies, like CDK4/6 inhibitors and antibody-drug conjugates, via rationalized combinations.

The future of breast cancer therapy lies in combination strategies that are developed via molecular profiling and guided by resistance biomarkers. Integrative, biomarker-driven treatment approaches will provide a rationalized and likely more effective means of treating advanced and refractory breast cancer in our effort to improve patient outcomes in a targeted and personalized approach.