Data from Genomic and Molecular Screenings Identify Different Mechanisms for Acquired Resistance to MET Inhibitors in Lung Cancer Cells

<div>Abstract<p>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 <i>MET</i> 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 <i>KIRREL, HDAC11, HIATL1</i>, and <i>MAPK1IP1L</i> genes, among others. In the other group, some cells have acquired inactivation of neurofibromatosis type 2 (<i>NF2</i>) concomitantly with strong overexpression of <i>NRG1</i> and a mutational profile that includes changes in <i>LMLN</i> and <i>TOMM34</i>. 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 <i>NF2</i> during acquisition of resistance to MET-TKI that may explain the refractoriness to erlotinib in these cells. <i>Mol Cancer Ther; 16(7); 1366–76. ©2017 AACR</i>.</p></div>