Inhibition of Hsp90 down-regulates mutant epidermal growth factor receptor (EGFR) expression and sensitizes EGFR mutant tumors to paclitaxel Journal Article

   

Authors:	Sawai, A.; Chandarlapaty, S.; Greulich, H.; Gonen, M.; Ye, Q.; Arteaga, C. L.; Sellers, W.; Rosen, N.; Solit, D. B.
Article Title:	Inhibition of Hsp90 down-regulates mutant epidermal growth factor receptor (EGFR) expression and sensitizes EGFR mutant tumors to paclitaxel
Abstract:	Mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are found in a subset of patients with lung cancer and correlate with response to EGFR tyrosine kinase inhibitors (TKI). Resistance to these agents invariably develops, and current treatment strategies have limited efficacy in this setting. Hsp90 inhibitors, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG), induce the degradation of EGFR and other Hsp90 interacting proteins and may thus have utility in tumors dependent upon sensitive Hsp90 clients. We find that the EGFR mutations found most commonly in patients with lung adenocarcinoma who respond to EGFR TKIs are potently degraded by 17-AAG. Although the expression of wild-type EGFR was also down-regulated by 17-AAG, its degradation required higher concentrations of drug and a longer duration of drug exposure. In animal models, a single dose of 17-AAG was sufficient to induce degradation of mutant EGFR and inhibit downstream signaling. 17-AAG treatment, at its maximal tolerated dose, caused a significant delay in H3255 (L858R EGFR) xenograft growth but was less effective than the EGFR TKI gefitinib. 17-AAG alone delayed, but did not completely inhibit, the growth of H1650 and H1975 xenografts, two EGFR mutant models which show intermediate and high levels of gefitinib resistance. 17-AAG could be safely coadministered with paclitaxel, and the combination was significantly more effective than either drug alone. These data suggest that Hsp90 inhibition in combination with chemotherapy may represent an effective treatment strategy for patients whose tumors express EGFR kinase domain mutations, including those with de novo and acquired resistance to EGFR TKIs. ©2008 American Association for Cancer Research.
Keywords:	controlled study; protein expression; unclassified drug; gene mutation; human cell; genetics; drug tolerability; cancer growth; drug potentiation; drug safety; nonhuman; paclitaxel; antineoplastic agent; mutant protein; protein domain; mouse; animal; animals; mice; animal tissue; drug inhibition; proto oncogene; tumor volume; protein kinase inhibitor; protein degradation; lung non small cell cancer; carcinoma, non-small-cell lung; lung neoplasms; epidermal growth factor receptor; animal experiment; animal model; antineoplastic agents, phytogenic; down-regulation; tumor xenograft; drug effect; drug resistance; drug screening; drug resistance, neoplasm; tumor cells, cultured; xenograft model antitumor assays; drug synergism; protein kinase inhibitors; lung tumor; gene expression regulation; gene expression regulation, neoplastic; drug antagonism; lung adenocarcinoma; cell culture; nude mouse; mice, nude; tumor burden; gefitinib; tanespimycin; heat shock protein 90; hsp90 heat-shock proteins; down regulation; mutant proteins; cell level; cell strain 3t3; nih 3t3 cells; epidermal growth factor receptor kinase; benzoquinones; lactams, macrocyclic; epidermal growth factor receptor kinase inhibitor; geldanamycin; 17-(allylamino)-17-demethoxygeldanamycin; benzoquinone derivative; macrocyclic lactam; genes, erbb-1; 17 allylamino 17 demathoxygeldanamycin
Journal Title:	Cancer Research
Volume:	68
Issue:	2
ISSN:	0008-5472
Publisher:	American Association for Cancer Research
Date Published:	2008-01-15
Start Page:	589
End Page:	596
Language:	English
DOI:	10.1158/0008-5472.can-07-1570
PUBMED:	18199556
PROVIDER:	scopus
PMCID:	PMC4011195
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-39049150922&partnerID=40&md5=e099d556b65e0ddb36df9301c5a1018e
Notes:	--- - "Cited By (since 1996): 35" - "Export Date: 17 November 2011" - "CODEN: CNREA" - "Source: Scopus"

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