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Research News at Vanderbilt

Probing mutant EGF receptor regulation

by | Posted on Thursday, Oct. 10, 2013 — 8:00 AM

Lung cancer cells often have mutations in the EGF receptor. (Wellcome Images)

Mutations in the epidermal growth factor receptor (EGFR) are found in many lung cancers. Certain EGFR mutants render tumors sensitive to the targeted therapies gefitinib and erlotinib, but the tumors eventually acquire resistance.

William Pao, M.D., Ph.D., Monica Red Brewer, Ph.D., and colleagues used biochemical and structural studies to determine whether mutant EGFRs in lung cancer adhere to the established mechanism for EGFR activation. This mechanism involves an asymmetric interaction between two receptor molecules, with a “donor” contacting – and activating – an “acceptor.” The investigators found that mutated EGFRs do use asymmetric dimerization, but that the oncogenic mutant receptors preferentially assume the “acceptor” role when co-expressed with wild-type EGFR. This “super-acceptor” activity leads to hyperphosphorylation and activation of wild-type EGFR, and also the related ErbB-2 family member.

The findings, reported Sept. 17 in the Proceedings of the National Academy of Sciences, have implications for understanding mechanisms of drug sensitivity and resistance in EGFR mutant lung cancers, which could be exploited for therapeutic benefit.

This research was supported in part by grants from the V Foundation and from the National Institutes of Health (CA121210, CA129243, CA143798, CA116020, CA154303, CA079992).

Contact:
Leigh MacMillan, (615) 322-4747
leigh.macmillan@vanderbilt.edu


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