Promising Marker for Response to EGFR Inhibitors

The ratio of two protein levels may predict clinical benefit of oral epidermal growth factor receptor (EGFR) inhibitors. Low levels of a protein called Mig6 (mitogen-inducible gene 6) and high levels of EGFR corresponded to a higher clinical response rate and progression-free survival in a small prospective cohort of lung cancer patients treated with the EGFR-inhibitor gefitinib.

The results, published in PLoS One, are still preliminary but suggest Mig6 protein levels as a potential predictive biomarker of response.

Gefitinib and erlotinib are two oral EGFR inhibitors approved by the US Food and Drug Administration for lung and pancreatic cancer patients. Predicting whether a patient will respond to EGFR-inhibition therapy remains difficult and only a minority of patients appear to be sensitive to anti-EGFR treatment. Only a small proportion of lung patients, those harboring exon 19 or exon 21 mutations (which result in high levels of the EGFR protein) are known to respond to erlotinib. No biomarkers have yet been identified for pancreatic cancer patients.

David Sidransky MD, director of head and neck cancer research and professor of oncology at Johns Hopkins, and colleagues identified upregulation of Mig6 corresponded to lower EGFR activity in cancer cell lines derived from patients that were resistance to EGFR-inhibitor treatment. Prostate, lung, bladder, and head and neck cancer cell lines with a range of resistance to EGFR inhibition were tested. The ratio of Mig6 to EGFR protein levels was more predictive of tumor cell response to the EGFR-inhibitor erlotinib compared with protein expression of either Mig6 or EGFR alone, the authors concluded.

The researchers confirmed their results in preclinical experiments and mouse models in a small cohort of 34 lung cancer patients treated with gefitinib. Results from this small dataset suggest that patients with a lower Mig6 to EGFR protein expression ratio are more responsive to gefitinib therapy. Of 18 patients who had a low ratio of Mig6 to EGFR, 10 (56%) had a partial response or stable disease compared with 1 of 16 (6.3%) of patients in the high ratio group who had a partial response or stable disease (P < .001).

Activation of the PI3 kinase pathway in the absence of EGFR signaling is thought to be a mechanism of resistance to EGFR inhibitors. Cell lines with high Mig6 protein levels, a known negative regulator of EGFR activity, had higher PI3K-AKT signaling activity, the study showed.

The authors also examined Mig6 levels in human lung and pancreatic tumors xenografted into mice. These xenografts, according to the authors, are reflective of human tumors as the grafting includes the stromal cells that make up the tumor microenvironment. An increase in Mig6 levels corresponded with resistance to EGFR treatment.

“As an approach to personalized therapy, the expression levels of both EGFR and Mig6 could be examined in tumor cells, and the ratio of the two molecules could be used to select patients who are likely to benefit from anti-EGFR therapy,” conclude the authors. The ratio of expression could also be used to assay for acquired drug resistance during therapy. Sidransky and co-authors are currently starting follow-up studies with larger cohorts of patients treated with EGFR inhibitors.