Genomic and Molecular Screenings Identify Different Mechanisms for Acquired Resistance to MET Inhibitors in Lung Cancer Cells
| العنوان: | Genomic and Molecular Screenings Identify Different Mechanisms for Acquired Resistance to MET Inhibitors in Lung Cancer Cells |
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| المؤلفون: | Manel Esteller, Jose Ramon Hernandez Mora, Sophia Derdak, Montse Sanchez-Cespedes, Anna Esteve-Codina, Diana Salinas-Chaparro, Eva Pros, Sebastian Moran, Ana Aza, David G. Pisano, Marc Dabad, Gonzalo Gómez-López, Pol Gimenez-Xavier, Osvaldo Graña, Ester Bonastre |
| المصدر: | Molecular Cancer Therapeutics. 16:1366-1376 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Lung Neoplasms, Biology, Erlotinib Hydrochloride, 03 medical and health sciences, 0302 clinical medicine, Gene expression, medicine, Humans, Lung cancer, Protein Kinase Inhibitors, Gene, PI3K/AKT/mTOR pathway, Cell Proliferation, Regulation of gene expression, Neurofibromin 2, Genomics, DNA Methylation, Proto-Oncogene Proteins c-met, medicine.disease, Molecular biology, respiratory tract diseases, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Oncology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Mutation, DNA methylation, Erlotinib, Tyrosine kinase, medicine.drug |
| الوصف: | The development of resistance to tyrosine kinase inhibitors (TKI) limits the long-term efficacy of cancer treatments involving them. We aimed to understand the mechanisms that underlie acquired resistance (AR) to MET inhibitors in lung cancer. EBC1 cells, which have MET amplification and are sensitive to TKIs against MET, were used to generate multiple clones with AR to a MET-TKI. Whole-exome sequencing, RNA sequencing, and global DNA methylation analysis were used to scrutinize the genetic and molecular characteristics of the resistant cells. AR to the MET-TKI involved changes common to all resistant cells, that is, phenotypic modifications, specific changes in gene expression, and reactivation of AKT, ERK, and mTOR. The gene expression, global DNA methylation, and mutational profiles distinguished at least two groups of resistant cells. In one of these, the cells have acquired sensitivity to erlotinib, concomitantly with mutations of the KIRREL, HDAC11, HIATL1, and MAPK1IP1L genes, among others. In the other group, some cells have acquired inactivation of neurofibromatosis type 2 (NF2) concomitantly with strong overexpression of NRG1 and a mutational profile that includes changes in LMLN and TOMM34. Multiple independent and simultaneous strategies lead to AR to the MET-TKIs in lung cancer cells. The acquired sensitivity to erlotinib supports the known crosstalk between MET and the HER family of receptors. For the first time, we show inactivation of NF2 during acquisition of resistance to MET-TKI that may explain the refractoriness to erlotinib in these cells. Mol Cancer Ther; 16(7); 1366–76. ©2017 AACR. |
| تدمد: | 1538-8514 1535-7163 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0bed3c22ea2fbd330a80ba75ce2c4013 https://doi.org/10.1158/1535-7163.mct-17-0104 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....0bed3c22ea2fbd330a80ba75ce2c4013 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15388514 15357163 |
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