1. ¹Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
2. ²Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

Correspondence: Dr L Neckers, Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Building 10/Clinical Research Center, room 1-5940, 9000 Rockville Pike, Bethesda, MD 20892-1107, USA. E-mail: len@helix.nih.gov

Revised 6 July 2007; Accepted 30 July 2007; Published online 21 August 2007.

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.