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

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Triple-Negative Breast Cancer (TNBC) is aggressive and heterogeneous, lacking targeted therapies.
• Chemotherapy resistance arises from cancer stem cells, metabolic plasticity, and the tumor microenvironment.
• Previous targeted therapies (e.g., PI3K/AKT/mTOR inhibitors) showed limited success due to resistance mechanisms and toxicity.

Purpose of the Study:

• To review the paradigm shift in TNBC treatment from 2021-2025.
• To highlight emerging precision medicine strategies beyond broad cytotoxicity.
• To discuss novel therapeutic modalities and combinatorial approaches for TNBC.

Main Methods:

• Review of recent advancements in TNBC targeted therapies.
• Analysis of synthetic lethality strategies targeting cell cycle checkpoints and mitotic kinases.
• Exploration of novel drug modalities like PROTACs and Antibody-Drug Conjugates (ADCs).

Main Results:

• Synthetic lethality approaches target G2/M checkpoint (WEE1, ATR) and mitotic kinases (PLK1, TTK) in TP53-mutant TNBC.
• PROTACs and ADCs enable targeting of previously undruggable kinases (TNIK, PTK7, PAK4).
• Combinatorial strategies show promise in overcoming therapeutic resistance.

Conclusions:

• TNBC treatment is evolving towards precision medicine, integrating novel kinase inhibitors, ADCs, and immunotherapies.
• Targeting genomic instability and previously inaccessible targets offers new therapeutic avenues.
• Future success in TNBC treatment relies on combinatorial approaches to overcome resistance and improve survival.