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Deep analysis of acquired resistance to FGFR1 inhibitor identifies MET and AKT activation and an expansion of AKT1 mutant cells

2018; Impact Journals LLC; Volume: 9; Issue: 59 Linguagem: Inglês

10.18632/oncotarget.25862

1949-2553

Pol Giménez‐Xavier, Eva Pros, Ana Aza, Sebastián Morán, Raúl Tonda, Anna Esteve‐Codina, Marc Dabad, Montse Sánchez‐Céspedes,

PI3K/AKT/mTOR signaling in cancer

// Pol Gimenez-Xavier 1, * , Eva Pros 1, * , Ana Aza 1 , Sebastian Moran 2 , Raul Tonda 3, 4 , Anna Esteve-Codina 3, 4 , Marc Dabad 3, 4 and Montse Sanchez-Cespedes 1 1 Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain 2 Cancer Epigenetics Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain 3 CNAG-CRG, Centre for Genomic Regulation (CRG) and Institute of Science and Technology (BIST), Barcelona, Spain 4 Universitat Pompeu Fabra (UPF), Barcelona, Spain * These authors contributed equally to this work Correspondence to: Montse Sanchez-Cespedes, email: mscespedes@idibell.cat Keywords: lung cancer; FGFR1; acquired resistance; tyrosine kinase inhibitor; cell lines Received: May 25, 2018 Accepted: July 16, 2018 Published: July 31, 2018 ABSTRACT 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.