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Bonastre EAuthorMoran SAuthorAza AAuthorDerdak SAuthorEsteve-Codina AAuthorDabad MCorresponding AuthorGenomic and molecular screenings identify different mechanisms for acquired resistance to MET inhibitors in lung cancer cells.
Publicated to:Molecular Cancer Therapeutics. 16 (7): 1366-1376 - 2017-07-01 16(7), DOI: 10.1158/1535-7163.mct-17-0104
Authors: Gimenez-Xavier, P; Pros, E; Bonastre, E; Moran, S; Aza, A; Graña, O; Gomez-Lopez, G; Derdak, S; Dabad, M; Esteve-Codina, A; Mora, JRH; Salinas-Chaparro, D; Esteller, M; Pisano, D; Sanchez-Cespedes, M
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Abstract
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.©2017 American Association for Cancer Research.
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Quality index
Bibliometric impact. Analysis of the contribution and dissemination channel
The work has been published in the journal Molecular Cancer Therapeutics due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2017, it was in position 43/223, thus managing to position itself as a Q1 (Primer Cuartil), in the category Oncology.
From a relative perspective, and based on the normalized impact indicator calculated from the Field Citation Ratio (FCR) of the Dimensions source, it yields a value of: 2.95, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: Dimensions Jul 2025)
Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-07-26, the following number of citations:
- WoS: 21
- Scopus: 25
- Europe PMC: 13
- Google Scholar: 13
Impact and social visibility
Leadership analysis of institutional authors
There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: Last Author (DABAD CASTELLA, MARC).
the author responsible for correspondence tasks has been DABAD CASTELLA, MARC.