The identification and development of cancer biomarkers to help identify patients most likely to benefit from Molecular Targeted Therapies is an important research focus for OSI Pharmaceuticals. OSI researchers and collaborators were seeking to understand why certain patients receive a greater benefit to erlotinib therapy. OSI scientists were among the first to observe and publish that EGFR tyrosine kinase inhibitor (TKI) sensitivity may be determined, in part, by the EMT-status of a tumor. Analysis of panels of tumor cell lines showed an association of EMT biomarker status with erlotinib sensitivity. Tumor cell lines expressing epithelial cell biomarkers showed the greatest sensitivity to the EGFR tyrosine kinase inhibitor, erlotinib.

Normal epithelial tissues use EGFR signaling to promote proliferation. In epithelial-derived cancer cells, abnormal activation of this pathway promotes tumor expansion and invasion. These epithelial-like tumor cells are sensitive in vitro to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as erlotinib. These epithelial-like tumor cells express biomarkers associated with the epithelial phenotype such as E-cadherin and other epithelial-cell associated biomarkers, but low or no biomarkers associated with the mesenchymal phenotype such as vimentin. As epithelial-like tumor cells undergo EMT and express the mesenchymal-like phenotype, the EMT associated cellular transitions and cellular interactions have profound consequences on EGFR signaling networks, as well as on the dependence of carcinoma cells on EGFR signals for migration and survival. For example, tumor cells that have acquired a more mesenchymal-like phenotype have shown decreased dependence on EGFR signaling, increased invasion and metastasis, resistance to chemotherapy and resistance to radiation-induced DNA damage. During EMT in non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic carcinoma, mesenchymal cells appear to acquire abnormal EGFR-independent survival signals to escape apoptosis during detachment (ie anoikis) and migration. The clinical potential of these EMT observations was demonstrated in a retrospective analysis of tumor samples from lung cancer patients in the clinical trial TRIBUTE. In the TRIBUTE study, the subgroup of patients who had tumors which expressed an EMT epithelial biomarker showed a significant benefit to treatment with erlotinib in combination with chemotherapy when compared with the group of patients who received only chemotherapy.

References

1. Buck E et al. Loss of homotypic cell adhesion by epithelial-mesenchymal transition or mutation limits sensitivity to epidermal growth factor receptor inhibition. Mol Cancer Ther. 2007; 6:532-541.
2. Thomson S et al. Epithelial-mesenchymal transition is a determinant in the sensitivity of non-small cell lung cancer cell lines to xenografts to epidermal growth factor inhibition. Cancer Res 2005;65(20):9455-9462
3. Yauch RL et al. Epithelial versus mesenchymal phenotype determines in viro sensitivity and predicts clinical activity of erlotinib in lung cancer patients. Clin Cancer Res 2005; 11(24); 8686-8698