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Updated: Nov 19, 2025

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
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The HSP-RTK-Akt axis mediates acquired resistance to Ganetespib in HER2-positive breast cancer

Christopher E Eyermann1, John D Haley1, Evguenia M Alexandrova2

  • 1Department of Pathology, Stony Brook University, Stony Brook, NY, 11794-8691, USA.

Cell Death & Disease
|January 27, 2021
PubMed

Insights

Ganetespib effectively suppresses HER2-positive breast cancer but acquired resistance emerges. Targeting Akt alongside Ganetespib may overcome this resistance, improving therapeutic strategies for breast cancer patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • HER2-positive breast cancer is aggressive and often develops resistance to targeted therapies.
  • Ganetespib, a Heat Shock Protein 90 (Hsp90) inhibitor, shows promise against HER2-positive breast cancer, including resistant cases.
  • Acquired resistance to Ganetespib is a significant challenge for its clinical application.

Purpose of the Study:

  • To investigate the mechanisms of acquired resistance to Ganetespib in HER2-positive breast cancer.
  • To identify actionable targets to overcome Ganetespib resistance.
  • To evaluate the therapeutic potential of combining Ganetespib with Akt inhibition.

Main Methods:

  • Utilized genetic mouse models of HER2-positive breast cancer treated with Ganetespib.
  • Analyzed molecular changes in Ganetespib-resistant tumors, including Heat Shock Proteins (HSPs) and receptor tyrosine kinases (RTKs).
  • Assessed the role of Akt signaling in resistance and tested the efficacy of Akt pharmacological inhibition.

Main Results:

  • Ganetespib treatment led to temporary tumor suppression followed by acquired resistance in mouse models.
  • Resistant tumors exhibited upregulation of compensatory HSPs and phospho-activated RTKs, with Akt stabilization and activation.
  • Pharmacological inhibition of Akt significantly delayed acquired Ganetespib resistance by 50%.

Conclusions:

  • Akt acts as a crucial actionable node downstream of the HSP/p-RTK resistance network.
  • Co-targeting Akt with Ganetespib presents a promising therapeutic strategy to overcome acquired resistance in HER2-positive breast cancer.
  • This combination approach may improve clinical outcomes for patients with refractory or resistant HER2-positive breast cancer.

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