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.
Highlights
Most novel therapeutic approaches in cancer are developed on the basis of our increasing knowledge of underlying oncogenic mutations
We confirmed that the various EBC1-resistant ( EBC1-R) cells were refractory to crizotinib treatment, another tyrosine kinase inhibitors (TKI) known to inhibit the tyrosine kinase activity of MET (Supplementary Fig. S1)
De novo mutations acquired at EGFR or ALK are not always associated with the acquired resistance (AR) to their respective TKIs, and alterations at other receptors with tyrosine kinase activity (RTK) or signal transduction molecules can account for the AR [15, 31, 32]
Summary
Most novel therapeutic approaches in cancer are developed on the basis of our increasing knowledge of underlying oncogenic mutations. In the case of lung cancer, our better understanding of its genetic architecture has enabled novel treatments to be designed, most of which are based on drugs that target growth factor receptors with tyrosine kinase activity (RTK) that are genetically activated in the tumors. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
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