MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling
Beth Israel Deaconess Medical Center · Harvard University · +8 more institutions
Abstract
The epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop drug resistance. Here, we describe a gefitinib-sensitive lung cancer cell line that developed resistance to gefitinib as a result of focal amplification of the MET proto-oncogene. inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 of 18 (22%) lung cancer specimens that had developed resistance to gefitinib or erlotinib. We find that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)-dependent activation of PI3K, a pathway…
Citation impact
- FWCI
- 174.38
- Percentile
- 100%
- References
- 22
Authors
19- JAJeffrey A. Engelman
Beth Israel Deaconess Medical Center, Harvard University, Massachusetts General Hospital, Dana-Farber Cancer Institute, Center for Systems Biology
- KZKreshnik Zejnullahu
Beth Israel Deaconess Medical Center, Harvard University, Massachusetts General Hospital, Dana-Farber Cancer Institute, Center for Systems Biology
- TMTetsuya Mitsudomi
Beth Israel Deaconess Medical Center, Harvard University, Massachusetts General Hospital, Dana-Farber Cancer Institute, Aichi Cancer Center, Center for Systems Biology
- YSYoungchul Song
Beth Israel Deaconess Medical Center, Harvard University, Massachusetts General Hospital, Dana-Farber Cancer Institute, Center for Systems Biology
- CHCourtney Hyland
Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, Harvard University, Massachusetts General Hospital, Dana-Farber Cancer Institute, Center for Systems Biology
Topics & keywords
- Gefitinib
- Erlotinib
- ERBB3
- Epidermal growth factor receptor
- Lung cancer
- Cancer research
- ErbB
- ERBB4
- Good health and well-being