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Inflaming resistance to Tarceva

A team at Cold Spring Harbor Laboratoryhas found that in cancer, inflammation-driven IL-6 signaling can cause resistance to drugs that inhibit epidermal growth factor receptor, such as Tarceva erlotinib and Iressa gefitinib.1The data suggest that blocking IL-6 could help treat drug-resistant cancers, a hypothesis Alder Biopharmaceuticals Inc. may put to the test in a Phase IIa trial of its anti-IL-6 antibody, ALD518.

About 80% of patients who respond to small molecule inhibitors of epidermal growth factor receptor (EGFR) carry oncogenic mutations in the kinase domain of the receptor that render them sensitive to EGFR inhibition.2 However, all patients will eventually develop resistance to these drugs.

Half of resistant cases stem from secondary mutations within EGFR or amplification of c-Met proto-oncogene (MET; HGFR). In the other half of cases, the mechanisms underlying resistance are unknown.

Thus, a team led by Raffaella Sordella, assistant professor at Cold Spring Harbor Laboratory, sought to identify new mechanisms of drug resistance. The researchers started by selecting EGFR mutant cell lines that were resistant to Tarceva but lacked any of the known mutations that confer resistance.

"We noticed these erlotinib-resistant cells

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