1. Academic Validation
  2. Inhibition of the T790M gatekeeper mutant of the epidermal growth factor receptor by EXEL-7647

Inhibition of the T790M gatekeeper mutant of the epidermal growth factor receptor by EXEL-7647

  • Clin Cancer Res. 2007 Jun 15;13(12):3713-23. doi: 10.1158/1078-0432.CCR-06-2590.
Steven B Gendreau 1 Richard Ventura Paul Keast A Douglas Laird F Michael Yakes Wentao Zhang Frauke Bentzien Belinda Cancilla Jeffery Lutman Felix Chu Lisa Jackman Yongchang Shi Peiwen Yu Jing Wang Dana T Aftab Christopher T Jaeger Stephanie M Meyer Anushka De Costa Kelly Engell Jason Chen Jean-Francois Martini Alison H Joly
Affiliations

Affiliation

  • 1 Exelixis, Inc., South San Francisco, California 94083, USA.
Abstract

Purpose: Agents inhibiting the epidermal growth factor receptor (EGFR) have shown clinical benefit in a subset of non-small cell lung Cancer patients expressing amplified or mutationally activated EGFR. However, responsive patients can relapse as a result of selection for EGFR gene mutations that confer resistance to ATP competitive EGFR inhibitors, such as erlotinib and gefitinib. We describe here the activity of EXEL-7647 (XL647), a novel spectrum-selective kinase inhibitor with potent activity against the EGF and vascular endothelial growth factor receptor tyrosine kinase families, against both wild-type (WT) and mutant EGFR in vitro and in vivo.

Experimental design: The activity of EGFR inhibitors against WT and mutant EGFRs and their effect on downstream signal transduction was examined in cellular assays and in vivo using A431 and MDA-MB-231 (WT EGFR) and H1975 (L858R and T790M mutant EGFR) xenograft tumors.

Results: EXEL-7647 shows potent and long-lived inhibition of the WT EGFR in vivo. In addition, EXEL-7647 inhibits cellular proliferation and EGFR pathway activation in the erlotinib-resistant H1975 cell line that harbors a double mutation (L858R and T790M) in the EGFR gene. In vivo efficacy studies show that EXEL-7647 substantially inhibited the growth of H1975 xenograft tumors and reduced both tumor EGFR signaling and tumor vessel density. Additionally, EXEL-7647, in contrast to erlotinib, substantially inhibited the growth and vascularization of MDA-MB-231 xenografts, a model which is more reliant on signaling through vascular endothelial growth factor receptors.

Conclusions: These studies provide a preclinical basis for clinical trials of XL647 in solid tumors and in patients bearing tumors that are resistant to existing EGFR-targeted therapies.

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