Deep analysis of acquired resistance to FGFR1 inhibitor identifies MET and AKT activation and an expansion of AKT1 mutant cells
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Pol Gimenez-Xavier1,*, Eva Pros1,*, Ana Aza1, Sebastian Moran2, Raul Tonda3,4, Anna Esteve-Codina3,4, Marc Dabad3,4 and Montse Sanchez-Cespedes1
1Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
2Cancer Epigenetics Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
3CNAG-CRG, Centre for Genomic Regulation (CRG) and Institute of Science and Technology (BIST), Barcelona, Spain
4Universitat Pompeu Fabra (UPF), Barcelona, Spain
*These authors contributed equally to this work
Montse Sanchez-Cespedes, email: firstname.lastname@example.org
Keywords: lung cancer; FGFR1; acquired resistance; tyrosine kinase inhibitor; cell lines
Received: May 25, 2018 Accepted: July 16, 2018 Published: July 31, 2018
The development of acquired resistance (AR) to tyrosine kinase inhibitors (TKIs) of FGFR1 activation is currently not well understood. To gain a deeper insight into this matter in lung cancer, we used the FGFR1-amplified DMS114 cell line and generated multiple clones with AR to an FGFR1-TKI. We molecularly scrutinized the resistant cells, using whole-exome sequencing, RNA sequencing and global DNA methylation analysis. Our results show a de novo activation of AKT and ERK, and a reactivation of mTOR. Furthermore, the resistant cells exhibited strong upregulation and activation of MET, indicating crosstalk between the FGFR1 and MET axes. The resistant cells also underwent a global decrease in promoter hypermethylation of the CpG islands. Finally, we observed clonal expansion of a pre-existing change in AKT1, leading to S266L substitution, within the kinase domain of AKT. Our results demonstrate that AR to FGFR1-TKI involves deep molecular changes that promote the activation of MET and AKT, coupled with common gene expression and DNA methylation profiles. The expansion of a substitution at AKT1 was the only shared genetic change, and this may have contributed to the AR.
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