The development of resistance to tyrosine kinase inhibitors (TKIs) 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, i.e., 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 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.
- Received January 31, 2017.
- Revision received April 1, 2017.
- Accepted April 3, 2017.
- Copyright ©2017, American Association for Cancer Research.