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Johns Hopkins Team Testing Marker to Predict Resistance to EGFR Inhibitors


Researchers from Johns Hopkins have identified a marker, Mig6, that in early studies has been able to predict longer survival among patients taking the EGFR tyrosine kinase inhibitors gefitinib (Astra Zeneca's Iressa) and erlotinib (Genenetech's Tarceva).

In a statement, the university said that the team -- led by Johns Hopkins oncology and genetics professor David Sidransky -- hopes to license the discovery to a biopharmaceutical company and collaborate with the firm to further develop the biomaker into a diagnostic test.

In the recent study, published in PLOS One, Sidransky and his colleagues identified Mig 6 as a predictor of response to EGFR inhibition in cell lines by tracking increases in Mig6 alongside the evolution of resistance to erlotinib.

In all of the six head and neck and prostate cancer cell lines the group assayed, Mig6 expression was strongly associated with lower levels of EGFR expression and resistance to erlotinib. Similar results were seen in 17 of 20 bladder and lung cancer cell lines.

While two lung cancer lines and one bladder cancer line bucked this curve, the study authors wrote that these outliers displayed very low EGFR expression compared to erlotinib-sensitive lines. According to the group, the results suggest overall that responsiveness to EGFR inhibitors could be better predicted in some tumor types by considering both EGFR and Mig6 expression than by using either of the markers alone.

The team replicated this finding in 22 mouse xenografts carrying four lung and 18 pancreatic tumors, finding that as Mig6 expression increased in the 18 pancreatic tumors, they also exhibited a more "erlotinib-resistant phenotype. "

The team also looked at Mig6 in a small group of patients treated with gefitinib (AstraZeneca’s Iressa), calculating ratios of Mig6 expression to EGFR expression. According to the study, the only two patients in the cohort who had partial response to the drug had low ratios: 0 and 0.14, and overall, patients with lower ratios had significantly better outcomes than the rest of the patients. Ten of 18 patients in the low-ratio group had either a partial response or stable disease, while only one of 16 in the high-ratio group avoided progression.

While other studies have found that targeting Mig6 might be a way to reverse EGFR inhibitor resistance, the Hopkins team study found that knocking down Mig6 did not markedly increase EGFR activity or alter sensitivity to erlotinib.

EGFR protein expression has not fared well in other studies as a reliable marker of responsiveness to EGFR inhibitors, according to the Hopkins team. The group's new results suggest that the activity of EGFR, rather than its overall expression may be a better indicator or predictor of sensitivity to these inhibitors

Though the results are preliminary, the team suggested that the ratio of Mig6 to EGFR could be used to predict which patients would benefit more from such drugs, as well as potentially track acquired resistance.