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Updated: Jan 13, 2026

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

Chang Hoon Lee1, Tuan Minh Nguyen1, Yongook Lee1

  • 1BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea.

International Journal of Molecular Sciences
|January 10, 2026
PubMed

Insights

Triple-Negative Breast Cancer (TNBC) treatment is shifting towards precision medicine. New strategies target genomic instability and previously undruggable targets, moving beyond traditional chemotherapy to combat resistance.

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.
Keywords:
PROTACPTK7antibody-drug conjugatesdrug resistancetriple-negative breast cancerundrugged kinome

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