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Heat shock protein 90 inhibition in lung cancer
Takeshi Shimamura1, Geoffrey I Shapiro
1Department of Medicine, Brigham and Women's Hospital and Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Abstract:
The heat shock protein 90 (Hsp90) chaperone is required for the conformational maturation and stability of multiple oncogenic kinases that drive signal transduction and proliferation of lung cancer cells. The recent demonstration that mutant epidermal growth factor receptor is an Hsp90 client, irrespective of the presence of the secondary threonine-to-methionine amino acid substitution mutation at position 790 mediating anilinoquinazoline resistance, suggests Hsp90 inhibition as a novel strategy against this group of lung cancers. The rarer epidermal growth factor receptors harboring exon 20 insertions and vIII mutations are also Hsp90 clients. Lung cancers may also be driven by mutant ErbB2, mutant B-Raf, or mutant or overexpressed c-Met, all of which are also degraded on Hsp90 inhibition. Hsp90 inhibitors may be synergistic with other drugs that disrupt chaperone function, including inhibitors of histone deacetylase 6 and the proteasome and agents that inhibit Hsp70 function. Hsp90 plays a unique antiapoptotic role in small cell lung cancer cells, so that Hsp90 inhibition results in substantial cell death in both chemosensitive and chemoresistant small cell lung cancer cell lines. Clinically, the geldanamycin compounds are the most mature, with manageable toxic effects. Several new classes of Hsp90 inhibitors are emerging, including purines and pyrazoles that have entered phase 1 trials. The available data suggest that Hsp90 inhibitors should be evaluated in multiple lung cancer subsets.
Insights
Heat shock protein 90 (Hsp90) inhibition is a promising strategy for lung cancer. Hsp90 inhibitors target multiple oncogenic drivers and show potential in various lung cancer types, including small cell lung cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Heat shock protein 90 (Hsp90) is crucial for the stability and function of oncogenic kinases driving lung cancer proliferation.
- Mutant epidermal growth factor receptor (EGFR), including resistance mutations, and other drivers like ErbB2, B-Raf, and c-Met, are Hsp90 clients.
- Hsp90 also has a critical anti-apoptotic role in small cell lung cancer (SCLC).
Purpose of the Study:
- To explore the potential of Hsp90 inhibition as a therapeutic strategy across diverse lung cancer subtypes.
- To identify specific oncogenic drivers dependent on Hsp90.
- To assess the synergistic potential of Hsp90 inhibitors with other therapeutic agents.
Main Methods:
- Review of existing data on Hsp90 client proteins in lung cancer.
- Analysis of Hsp90's role in signal transduction and proliferation pathways.
- Evaluation of Hsp90 inhibitor efficacy and toxicity, including clinical trial data.
Main Results:
- Hsp90 inhibition leads to the degradation of key oncogenic kinases, including mutant EGFR (regardless of resistance mutations), ErbB2, B-Raf, and c-Met.
- Hsp90 inhibition induces significant cell death in both chemosensitive and chemoresistant SCLC cell lines.
- Newer Hsp90 inhibitor classes (purines, pyrazoles) are entering clinical trials with manageable toxicity.
Conclusions:
- Hsp90 inhibition represents a viable therapeutic strategy for multiple lung cancer subsets, including those with specific EGFR mutations and SCLC.
- Combination therapies involving Hsp90 inhibitors and agents targeting chaperone function or proteasomal degradation may enhance efficacy.
- Further clinical evaluation of Hsp90 inhibitors across various lung cancer populations is warranted.
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