PMID- 26580964 OWN - NLM STAT- MEDLINE DCOM- 20160627 LR - 20181202 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 10 IP - 11 DP - 2015 TI - MET Gene Amplification and MET Receptor Activation Are Not Sufficient to Predict Efficacy of Combined MET and EGFR Inhibitors in EGFR TKI-Resistant NSCLC Cells. PG - e0143333 LID - 10.1371/journal.pone.0143333 [doi] LID - e0143333 AB - Epidermal growth factor receptor (EGFR), member of the human epidermal growth factor receptor (HER) family, plays a critical role in regulating multiple cellular processes including proliferation, differentiation, cell migration and cell survival. Deregulation of the EGFR signaling has been found to be associated with the development of a variety of human malignancies including lung, breast, and ovarian cancers, making inhibition of EGFR the most promising molecular targeted therapy developed in the past decade against cancer. Human non small cell lung cancers (NSCLC) with activating mutations in the EGFR gene frequently experience significant tumor regression when treated with EGFR tyrosine kinase inhibitors (TKIs), although acquired resistance invariably develops. Resistance to TKI treatments has been associated to secondary mutations in the EGFR gene or to activation of additional bypass signaling pathways including the ones mediated by receptor tyrosine kinases, Fas receptor and NF-kB. In more than 30-40% of cases, however, the mechanisms underpinning drug-resistance are still unknown. The establishment of cellular and mouse models can facilitate the unveiling of mechanisms leading to drug-resistance and the development or validation of novel therapeutic strategies aimed at overcoming resistance and enhancing outcomes in NSCLC patients. Here we describe the establishment and characterization of EGFR TKI-resistant NSCLC cell lines and a pilot study on the effects of a combined MET and EGFR inhibitors treatment. The characterization of the erlotinib-resistant cell lines confirmed the association of EGFR TKI resistance with loss of EGFR gene amplification and/or AXL overexpression and/or MET gene amplification and MET receptor activation. These cellular models can be instrumental to further investigate the signaling pathways associated to EGFR TKI-resistance. Finally the drugs combination pilot study shows that MET gene amplification and MET receptor activation are not sufficient to predict a positive response of NSCLC cells to a cocktail of MET and EGFR inhibitors and highlights the importance of identifying more reliable biomarkers to predict the efficacy of treatments in NSCLC patients resistant to EGFR TKI. FAU - Presutti, Dario AU - Presutti D AD - Institute of Cell Biology and Neurobiology, National Research Council, Campus Adriano Buzzati-Traverso, Monterotondo (Roma), Italy. FAU - Santini, Simonetta AU - Santini S AD - Institute of Cell Biology and Neurobiology, National Research Council, Campus Adriano Buzzati-Traverso, Monterotondo (Roma), Italy. FAU - Cardinali, Beatrice AU - Cardinali B AD - Institute of Cell Biology and Neurobiology, National Research Council, Campus Adriano Buzzati-Traverso, Monterotondo (Roma), Italy. FAU - Papoff, Giuliana AU - Papoff G AD - Institute of Cell Biology and Neurobiology, National Research Council, Campus Adriano Buzzati-Traverso, Monterotondo (Roma), Italy. FAU - Lalli, Cristiana AU - Lalli C AD - Institute of Cell Biology and Neurobiology, National Research Council, Campus Adriano Buzzati-Traverso, Monterotondo (Roma), Italy. FAU - Samperna, Simone AU - Samperna S AD - Institute of Cell Biology and Neurobiology, National Research Council, Campus Adriano Buzzati-Traverso, Monterotondo (Roma), Italy. FAU - Fustaino, Valentina AU - Fustaino V AD - Institute of Cell Biology and Neurobiology, National Research Council, Campus Adriano Buzzati-Traverso, Monterotondo (Roma), Italy. FAU - Giannini, Giuseppe AU - Giannini G AD - Department of Experimental Medicine, University La Sapienza, Roma, Italy. FAU - Ruberti, Giovina AU - Ruberti G AD - Institute of Cell Biology and Neurobiology, National Research Council, Campus Adriano Buzzati-Traverso, Monterotondo (Roma), Italy. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151118 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (KRAS protein, human) RN - 0 (Protein Kinase Inhibitors) RN - DA87705X9K (Erlotinib Hydrochloride) RN - EC 2.7.10.1 (ERBB2 protein, human) RN - EC 2.7.10.1 (ERBB3 protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.10.1 (Proto-Oncogene Proteins c-met) RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - EC 2.7.10.1 (Receptor, ErbB-3) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) RN - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) SB - IM MH - Base Sequence MH - Carcinogenesis/genetics MH - Carcinoma, Non-Small-Cell Lung/*genetics MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - *Drug Resistance, Neoplasm/drug effects MH - ErbB Receptors/*antagonists & inhibitors/genetics MH - Erlotinib Hydrochloride/pharmacology/therapeutic use MH - Extracellular Signal-Regulated MAP Kinases/metabolism MH - *Gene Amplification MH - Humans MH - Inhibitory Concentration 50 MH - Lung Neoplasms/*genetics MH - Molecular Sequence Data MH - Mutation/genetics MH - Phosphorylation/drug effects MH - Protein Kinase Inhibitors/chemistry/pharmacology/*therapeutic use MH - Proto-Oncogene Proteins c-met/*antagonists & inhibitors/*genetics MH - Proto-Oncogene Proteins p21(ras)/genetics MH - Receptor, ErbB-2/metabolism MH - Receptor, ErbB-3/metabolism MH - Treatment Outcome PMC - PMC4651538 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2015/11/19 06:00 MHDA- 2016/06/28 06:00 PMCR- 2015/11/18 CRDT- 2015/11/19 06:00 PHST- 2015/07/31 00:00 [received] PHST- 2015/11/03 00:00 [accepted] PHST- 2015/11/19 06:00 [entrez] PHST- 2015/11/19 06:00 [pubmed] PHST- 2016/06/28 06:00 [medline] PHST- 2015/11/18 00:00 [pmc-release] AID - PONE-D-15-33674 [pii] AID - 10.1371/journal.pone.0143333 [doi] PST - epublish SO - PLoS One. 2015 Nov 18;10(11):e0143333. doi: 10.1371/journal.pone.0143333. eCollection 2015.