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Co-targeting HSP90 alpha and CDK7 overcomes resistance against HSP90 inhibitors in BCR-ABL1+ leukemia cells

Melina Vogt1, Niklas Dienstbier1, Julian Schliehe-Diecks1

  • 1Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Cell Death & Disease
|December 6, 2023
PubMed

Insights

Heat shock protein 90 (HSP90) inhibitors show promise against leukemia, but resistance develops. Combining HSP90 inhibition with CDK7 inhibition overcomes resistance by blocking heat shock response and HSP90α overexpression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Heat shock protein 90 (HSP90) is a cancer target, but resistance limits HSP90 inhibitor (HSP90i) efficacy.
  • Heat shock response (HSR) is a key mechanism of HSP90i resistance.
  • Understanding HSP90 isoforms (α and β) and resistance mechanisms is vital for improving HSP90i therapy.

Purpose of the Study:

  • Investigate the roles of HSP90α and HSP90β in cancer cell growth and HSP90i resistance.
  • Identify mechanisms of acquired resistance to HSP90 inhibitors.
  • Develop strategies to overcome HSP90i resistance in leukemia.

Main Methods:

  • Multi-omics approaches to analyze HSP90 isoform function.
  • Genetic manipulation (ablation) of HSP90 isoforms.
  • Cellular and in vivo models of BCR-ABL1+ leukemia.
  • Drug resistance studies with various HSP90 inhibitors (PU-H71, Tanespimycin, Coumermycin A1).
  • Combination therapy studies (CDK7 and HSP90 inhibition).

Main Results:

  • HSP90β ablation induced HSP90α and extracellular HSP90α (eHSP90α) overexpression.
  • HSP90α absence restricted in vivo leukemia growth by downregulating PTPRC (CD45).
  • PU-H71 resistance involved HSP90AA1 gene amplification/mutation and HSP90α overexpression.
  • Tanespimycin/Coumermycin A1 resistance involved MDR1 efflux pump overexpression.
  • Combined CDK7 and HSP90 inhibition showed synergistic activity against resistant leukemia cells.

Conclusions:

  • Targeting HSP90 isoforms is crucial for leukemia treatment.
  • Acquired resistance to HSP90i can occur through distinct mechanisms, including HSP90α upregulation or MDR1 overexpression.
  • Combination therapy with CDK7 and HSP90 inhibitors offers a promising strategy to overcome resistance and enhance efficacy in BCR-ABL1+ leukemia.

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