Inflaming resistance to Tarceva

A team at Cold Spring Harbor Laboratory has 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.1 The 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 had a dramatically different morphology than erlotinib- sensitive cells,” Sordella told SciBX. “We performed gene expression profiling to understand what was different about them.”
Her team found that transforming growth factor-β (TGFB; TGFβ) was induced in resistant cells,explaining their difference in morphology. Moreover, IL-6 secretion from these cells was induced more than 10-fold, and the increase required TGFβ.
Adding IL-6 to erlotinib-sensitive cells increased their resistance to the drug compared with that of cells not given IL-6.
Sordella's team also examined non–small cell lung cancer (NSCLC) samples isolated from Tarceva-naïve patients and found that a subpopulation of cells had high levels of TGFβ and IL-6. That finding suggests some tumor cells may be intrinsically resistant to Tarceva.
Tarceva is marketed by Astellas Pharma Inc. and Roche's Genentech Inc. unit, whereas Iressa is marketed by AstraZeneca plc.



Cain, C. SciBX 3(35); doi:10.1038/scibx.2010.1056
Published online Sep. 9 2010