MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling Export

@article{citeulike:1284193, 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 thought to be specific to EGFR/ERBB family receptors. Thus, we propose that MET amplification may promote drug resistance in other ERBB-driven cancers as well. 10.1126/science.1141478}, address = {Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.}, author = {Engelman, Jeffrey A. and Zejnullahu, Kreshnik and Mitsudomi, Tetsuya and Song, Youngchul and Hyland, Courtney and Park, Joon O. and Lindeman, Neal and Gale, Christopher-Michael and Zhao, Xiaojun and Christensen, James and Kosaka, Takayuki and Holmes, Alison J. and Rogers, Andrew M. and Cappuzzo, Federico and Mok, Tony and Lee, Charles and Johnson, Bruce E. and Cantley, Lewis C. and Janne, Pasi A.}, citeulike-article-id = {1284193}, citeulike-linkout-0 = {http://dx.doi.org/10.1126/science.1141478}, citeulike-linkout-1 = {http://www.sciencemag.org/content/316/5827/1039.abstract}, citeulike-linkout-2 = {http://www.sciencemag.org/content/316/5827/1039.full.pdf}, citeulike-linkout-3 = {http://www.sciencemag.org/cgi/content/abstract/316/5827/1039}, citeulike-linkout-4 = {http://view.ncbi.nlm.nih.gov/pubmed/17463250}, citeulike-linkout-5 = {http://www.hubmed.org/display.cgi?uids=17463250}, day = {18}, doi = {10.1126/science.1141478}, issn = {1095-9203}, journal = {Science}, keywords = {amplification}, month = {May}, number = {5827}, pages = {1039--1043}, posted-at = {2007-06-07 04:45:33}, priority = {2}, title = {MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling}, url = {http://dx.doi.org/10.1126/science.1141478}, volume = {316}, year = {2007} }

TY - JOUR ID - citeulike:1284193 L3 - citeulike-article-id:1284193 N2 - 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 thought to be specific to EGFR/ERBB family receptors. Thus, we propose that MET amplification may promote drug resistance in other ERBB-driven cancers as well. 10.1126/science.1141478 IS - 5827 JF - Science SN - 1095-9203 AD - Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA. EP - 1043 TI - MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling VL - 316 SP - 1039 KW - amplification AU - Engelman, Jeffrey AU - Zejnullahu, Kreshnik AU - Mitsudomi, Tetsuya AU - Song, Youngchul AU - Hyland, Courtney AU - Park, Joon AU - Lindeman, Neal AU - Gale, Christopher-Michael AU - Zhao, Xiaojun AU - Christensen, James AU - Kosaka, Takayuki AU - Holmes, Alison AU - Rogers, Andrew AU - Cappuzzo, Federico AU - Mok, Tony AU - Lee, Charles AU - Johnson, Bruce AU - Cantley, Lewis AU - Janne, Pasi PY - 2007/05/18/ UR - http://dx.doi.org/10.1126/science.1141478 ER -