Journal
THORACIC CANCER
Volume 12, Issue 5, Pages 631-642Publisher
WILEY
DOI: 10.1111/1759-7714.13839
Keywords
acquired resistance; and heat shock protein 90; epidermal growth factor receptor; epidermal growth factor receptor amplification; epidermal growth factor receptor-tyrosine kinase inhibitor
Categories
Funding
- Bristol-Myers Squibb Foundation
- Kobayashi Foundation for Cancer Research
- Ministry of Education, Culture, Sports, Science and Technology
- Naito Foundation
- National Cancer Center Research and Development Fund [30-A-6]
- Novartis Foundation
- SGH Foundation
- Takeda Science Foundation
- Novartis Foundation Grant
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EGFR amplification confers resistance to third-generation EGFR-TKIs, but can be overcome by HSP90 inhibition. The study results provide a preclinical rationale for using HSP90 inhibitors to overcome EGFR amplification-mediated resistance.
Background: Patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations are sensitive to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) but inevitably develop resistance to the inhibitors mostly through acquisition of the secondary T790M mutation. Although third-generation EGFR-TKIs overcome this resistance by selectively inhibiting EGFR with EGFR-TKI-sensitizing and T790M mutations, acquired resistance to third-generation EGFR-TKIs invariably develops. Methods: Next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) analysis were performed in an EGFR T790M-mutated NSCLC patient who had progressed after a third-generation EGFR-TKI, TAS-121. EGFR-mutated cell lines were subjected to a cell proliferation assay and western blotting analysis with EGFR-TKIs and a heat shock protein 90 (HSP90) inhibitor. Results: NGS and FISH analysis revealed EGFR amplification in the resistant cancer cells. While EGFR L858R/T90M-mutated cell line was sensitive to osimertinib or TAS-121 in vitro, EGFR-overexpressing cell lines displayed resistance to these EGFR-TKIs. Western blot analysis showed that EGFR phosphorylation and overexpression of EGFR in cell lines was not suppressed by third-generation EGFR-TKIs. In contrast, an HSP90 inhibitor reduced total and phosphorylated EGFR and inhibited the proliferation of resistant cell lines. Conclusions: EGFR amplification confers resistance to third-generation EGFR-TKIs which can be overcome by HSP90 inhibition. The results provide a preclinical rationale for the use of HSP90 inhibitors to overcome EGFR amplification-mediated resistance.
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