HSP90 inhibition overcomes EGFR amplification‐induced resistance to third‐generation EGFR‐TKIs. Issue 5 (20th January 2021)

• Record Type: Journal Article
• Authors: Watanabe, Sho; Goto, Yasushi; Yasuda, Hiroyuki; Kohno, Takashi; Motoi, Noriko; Ohe, Yuichiro; Nishikawa, Hiroyoshi; Kobayashi, Susumu S.; Kuwano, Kazuyoshi; Togashi, Yosuke
• Is Part Of: Thoracic cancer. Volume 12:Issue 5(2021)
• Page Start: 631
• Page End: 642
• Publication Date: 2021-01-20
• Subjects: acquired resistance -- and heat shock protein 90 -- epidermal growth factor receptor -- epidermal growth factor receptor amplification -- epidermal growth factor receptor‐tyrosine kinase inhibitor; Chest -- Cancer -- Periodicals; Chest -- Cancer -- Treatment -- Periodicals; Chest -- Surgery -- Periodicals; 616.99494005
• DOI: 10.1111/1759-7714.13839
• Languages: English
• ISSNs: 1759-7706

Abstract

Abstract: 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. Abstract : Third‐generation EGFR‐TKIs overcome EGFR T790M‐meditated resistance. However, amplified EGFR confers resistance to third‐generation EGFR‐TKIs. Inhibiting HSP90, a chaperon for EGFR, suppresses the proliferation of EGFR‐amplified cells by degrading EGFR in vitro, providing a preclinical rationale for the use of HSP90 inhibitors to overcome the EGFR amplification‐meditated resistance.