Sensitivity of epidermal growth factor receptor and ErbB2 exon 20 insertion mutants to Hsp90 inhibition.
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.
Xu
W
W
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-1107, USA.
Soga
S
S
Beebe
K
K
Lee
M-J
MJ
Kim
Y S
YS
Trepel
J
J
Neckers
L
L
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
D000970:Antineoplastic Agents; D066246:ErbB Receptors; D018841:HSP90 Heat-Shock Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases
Nat Struct Mol Biol. 2005 Feb;12(2):120-6
15643424
Cancer Res. 2004 Dec 15;64(24):8919-23
15604253
Cancer Res. 2005 Mar 1;65(5):1642-6
15753357
J Clin Oncol. 2005 Apr 10;23(11):2513-20
15738541
Anticancer Drugs. 2005 Jul;16(6):601-7
15930886
N Engl J Med. 2005 Jul 14;353(2):133-44
16014883
Cancer Res. 2005 Jul 15;65(14):6401-8
16024644
PLoS Med. 2005 Nov;2(11):e313
16187797
Clin Cancer Res. 2006 Mar 1;12(5):1647-53
16533793
Mol Syst Biol. 2005;1:2005.0008
16729043
Hum Pathol. 2006 Jun;37(6):755-63
16733218
Cancer Res. 2006 Jul 1;66(13):6487-91
16818618
Cancer Cell. 2006 Jul;10(1):25-38
16843263
Int J Cancer. 2006 Dec 1;119(11):2586-91
16988931
Cancer Sci. 2007 Mar;98(3):357-63
17270025
J Biol Chem. 2001 Feb 2;276(5):3702-8
11071886
Cell Stress Chaperones. 2002 Jan;7(1):91-6
11892991
N Engl J Med. 2004 May 20;350(21):2129-39
15118073
Science. 2004 Jun 4;304(5676):1497-500
15118125
Nature. 2004 Sep 30;431(7008):525-6
15457249
J Biol Chem. 1996 Mar 1;271(9):4974-7
8617772
J Biol Chem. 1996 Sep 13;271(37):22796-801
8798456
J Natl Cancer Inst. 2005 Mar 2;97(5):339-46
15741570