Genomic and molecular screenings unveil different mechanisms for acquired resistance to MET inhibitors in lung cancer cells

Acquired resistance (AR) is a major hurdle in lung cancer treatment and it is an important drawback in tyrosine kinase inhibitors (TKIs)-based therapeutics. In this context, it is important to unravel the molecular determinants underlying this phenomenon. Our results show molecularly different clones arising during AR to the MET-TKI, many of them involving sensitivity to erlotinib, which supports the known biological crosstalk between MET and the HER-family of receptors. We have also identified inactivation of NF2 in one of the erlotinib-resistant clones. Collectively our findings evidence that AR promote the expansion of multiple subclonal populations with distinct genetic and molecular characteristics highlighting the importance of considering combinatorial therapeutics when designing strategies for second-line treatments in TKI-treated lung cancer patients. The EBC1 cells, which 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.