The relative expression of Mig6 and EGFR is associated with resistance to EGFR kinase inhibitors.

Abstract

The sensitivity of only a few tumors to anti-epidermal growth factor receptor EGFR tyrosine kinase inhibitors (TKIs) can be explained by the presence of EGFR tyrosine kinase (TK) domain mutations. In addition, such mutations were rarely found in tumor types other than lung, such as pancreatic and head and neck cancer. In this study we sought to elucidate mechanisms of resistance to EGFR-targeted therapies in tumors that do not harbor TK sensitizing mutations in order to identify markers capable of guiding the decision to incorporate these drugs into chemotherapeutic regimens. Here we show that EGFR activity was markedly decreased during the evolution of resistance to the EGFR tyrosine kinase inhibitor (TKI) erlotinib, with a concomitant increase of mitogen-inducible gene 6 (Mig6), a negative regulator of EGFR through the upregulation of the PI3K-AKT pathway. EGFR activity, which was more accurately predicted by the ratio of Mig6/EGFR, highly correlated with erlotinib sensitivity in panels of cancer cell lines of different tissue origins. Blinded testing and analysis in a prospectively followed cohort of lung cancer patients treated with gefitinib alone demonstrated higher response rates and a marked increased in progression free survival for patients with a low Mig6/EGFR ratio (approximately 100 days, P = 0.01).

• Authors: Xiaofei Chang, Eugene Izumchenko, Luisa M Solis, Myoung Sook Kim, Aditi Chatterjee, Shizhang Ling, Constance L Monitto, Paul M Harari, Manuel Hidalgo, Steve N Goodman, Ignacio I Wistuba, Atul Bedi, David Sidransky
• Journal: PloS one (PLoS One) Vol. 8 Issue 7 Pg. e68966 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23935914 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• ERRFI1 protein, human
• Protein Kinase Inhibitors
• Quinazolines
• Tumor Suppressor Proteins
• Erlotinib Hydrochloride
• EGFR protein, human
• ErbB Receptors
• Proto-Oncogene Proteins c-akt
• Gefitinib

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Animals
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, metabolism)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects, genetics)
• ErbB Receptors (antagonists & inhibitors, genetics, metabolism)
• Erlotinib Hydrochloride
• Female
• Gefitinib
• Humans
• Immunoblotting
• Kaplan-Meier Estimate
• Lung (drug effects, metabolism, pathology)
• Lung Neoplasms (drug therapy, genetics, metabolism)
• Male
• Mice
• Middle Aged
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-akt (metabolism)
• Quinazolines (pharmacology, therapeutic use)
• RNA Interference
• Signal Transduction (drug effects)
• Tumor Suppressor Proteins (genetics, metabolism)
• Xenograft Model Antitumor Assays