title: Sensitivity of epidermal growth factor receptor and ErbB2 exon 20 insertion mutants to Hsp90 inhibition.
abstract: The mature epidermal growth factor receptor (EGFR) neither associates with nor requires the molecular chaperone heat-shock protein 90 (Hsp90). Mutations in EGFR exons 18, 19, and 21 confer Hsp90 chaperone dependence. In non-small cell lung cancer (NSCLC), these mutations are associated with enhanced sensitivity to EGFR inhibitors in vitro and with clinical response in vivo. Although less prevalent, insertions in EGFR exon 20 have also been described in NSCLC. These mutations, however, confer resistance to EGFR inhibitors. In NSCLC, exon 20 insertions have also been identified in the EGFR family member ErbB2. Here, we examined the sensitivity of exon 20 insertion mutants to an Hsp90 inhibitor currently in the clinic. Our data demonstrate that both EGFR and ErbB2 exon 20 insertion mutants retain dependence on Hsp90 for stability and downstream-signalling capability, and remain highly sensitive to Hsp90 inhibition. Use of Hsp90 inhibitors should be considered in NSCLC harbouring exon 20 insertions in either EGFR or ErbB2.
authors: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-1107, USA.
authors: W
authors: W
authors: Xu
authors: S
authors: S
authors: Soga
authors: K
authors: K
authors: Beebe
authors: M-J
authors: MJ
authors: Lee
authors: Y S
authors: YS
authors: Kim
authors: J
authors: J
authors: Trepel
authors: L
authors: L
authors: Neckers
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019556:COS Cells; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D002522:Chlorocebus aethiops; D066246:ErbB Receptors / Q000187:drug effects* / Q000235:genetics*; D005091:Exons; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy; D009154:Mutation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D018841:HSP90 Heat-Shock Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases
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