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Updated: Apr 9, 2026
Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
Published on: January 20, 2023
Resistance to HSP90 inhibition involving loss of MCL1 addiction
S Busacca1, E W P Law1, I R Powley2
1Department of Cancer Studies, Cancer Research UK Leicester Centre, University of Leicester, Leicester, UK.
Abstract:
Inhibition of the chaperone heat-shock protein 90 (HSP90) induces apoptosis, and it is a promising anti-cancer strategy. The mechanisms underpinning apoptosis activation following HSP90 inhibition and how they are modified during acquired drug resistance are unknown. We show for the first time that, to induce apoptosis, HSP90 inhibition requires the cooperation of multi BH3-only proteins (BID, BIK, PUMA) and the reciprocal suppression of the pro-survival BCL-2 family member MCL1, which occurs via inhibition of STAT5A. A subset of tumour cell lines exhibit dependence on MCL1 expression for survival and this dependence is also associated with tumour response to HSP90 inhibition. In the acquired resistance setting, MCL1 suppression in response to HSP90 inhibitors is maintained; however, a switch in MCL1 dependence occurs. This can be exploited by the BH3 peptidomimetic ABT737, through non-BCL-2-dependent synthetic lethality.
Insights
Heat-shock protein 90 (HSP90) inhibition triggers cancer cell death by engaging multiple proteins and suppressing MCL1. Acquired resistance involves a shift in MCL1 dependence, exploitable by ABT737.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Biology
Background:
- Heat-shock protein 90 (HSP90) inhibition is a promising anti-cancer strategy.
- Mechanisms of apoptosis induction by HSP90 inhibition and acquired resistance are poorly understood.
Purpose of the Study:
- To elucidate the mechanisms of apoptosis activation by HSP90 inhibition.
- To investigate how these mechanisms are altered during acquired drug resistance.
Main Methods:
- Investigated the role of BH3-only proteins (BID, BIK, PUMA) and MCL1 in HSP90 inhibition-induced apoptosis.
- Analyzed STAT5A's role in MCL1 suppression.
- Examined MCL1 dependence in tumor cell lines and acquired resistance models.
- Assessed the efficacy of BH3 peptidomimetic ABT737 in acquired resistance.
Main Results:
- HSP90 inhibition requires multiple BH3-only proteins and MCL1 suppression via STAT5A inhibition to induce apoptosis.
- Tumor cell lines dependent on MCL1 expression show sensitivity to HSP90 inhibition.
- Acquired resistance maintains MCL1 suppression but alters dependence, making it susceptible to ABT737 via non-BCL-2-dependent synthetic lethality.
Conclusions:
- HSP90 inhibition-induced apoptosis involves a complex interplay of BH3-only proteins and MCL1 suppression.
- MCL1 dependence is a key factor in tumor response to HSP90 inhibition.
- Targeting MCL1 dependence with agents like ABT737 offers a strategy to overcome acquired resistance to HSP90 inhibitors.
