Overcoming Therapeutic Resistance in Triple-Negative Breast Cancer: Targeting the Undrugged Kinome

Triple-Negative Breast Cancer (TNBC) remains the most aggressive breast cancer subtype, characterized by profound heterogeneity and a lack of effective targeted therapies. Although cytotoxic chemotherapy is the standard of care, the rapid emergence of resistance driven by cancer stem cells (CSCs), metabolic plasticity, and the tumor microenvironment limits long-term survival. This review highlights the paradigm shift in TNBC treatment from 2021 to 2025, moving beyond broad cytotoxicity to precision medicine. We first examine the limitations of earlier targeted therapies, such as PI3K/AKT/mTOR inhibitors, which failed due to compensatory feedback loops and toxicity. We then discuss emerging synthetic lethality strategies targeting the G2/M checkpoint (WEE1, ATR) and mitotic kinases (PLK1, TTK) to exploit genomic instability in TP53-mutant tumors. Furthermore, we explore how novel modalities like PROTACs and Antibody–Drug Conjugates (ADCs) are unlocking the “undrugged kinome,” including targets like TNIK, PTK7, and PAK4, which were previously inaccessible. Finally, we propose that future success lies in combinatorial strategies integrating these next-generation kinase inhibitors with ADCs and immunotherapies to dismantle therapeutic resistance.