Deep analysis of acquired resistance to FGFR1 inhibitor identifies MET and AKT activation and an expansion of AKT1 mutant cells
Mostra el registre complet Registre parcial de l'ítem
- dc.contributor.author Giménez Xavier, Pol
- dc.contributor.author Pros, Eva
- dc.contributor.author Aza, Ana
- dc.contributor.author Moran, Sebastian
- dc.contributor.author Tonda, Raúl
- dc.contributor.author Esteve-Codina, Anna
- dc.contributor.author Dabad, Marc
- dc.contributor.author Sánchez Céspedes, Montse
- dc.date.accessioned 2019-11-27T08:34:33Z
- dc.date.available 2019-11-27T08:34:33Z
- dc.date.issued 2018
- dc.description.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.
- dc.description.sponsorship This work was supported by Spanish grants SAF2014-54571-R (to M Sanchez-Cespedes), AGAUR (Agency for Management of University and Research Grants) (2014SGR641) (to M Sanchez-Cespedes), and PTA2014-09515 (to M Dabad). The CNAG-CRG laboratory is a member of the Spanish National Bioinformatics Institute (INB), PRB2-ISCIII and is supported by grants PT13/0001, from the PE I+D+i 2013-2016, funded by ISCIII and FEDER (to A Esteve-Codina).
- dc.format.mimetype application/pdf
- dc.identifier.citation Gimenez-Xavier P, Pros E, Aza A, Moran S, Tonda R, Esteve-Codina A et al. Deep analysis of acquired resistance to FGFR1 inhibitor identifies MET and AKT activation and an expansion of AKT1 mutant cells. Oncotarget. 2018; 9(59):31549-58. DOI: 10.18632/oncotarget.25862
- dc.identifier.doi http://dx.doi.org/10.18632/oncotarget.25862
- dc.identifier.issn 1949-2553
- dc.identifier.uri http://hdl.handle.net/10230/43004
- dc.language.iso eng
- dc.publisher Impact Journals
- dc.relation.ispartof Oncotarget. 2018; 9(59):31549-58
- dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2014-54571-R
- dc.rights © Gimenez-Xavier et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0) (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/by/3.0/
- dc.subject.keyword Lung cancer
- dc.subject.keyword FGFR1
- dc.subject.keyword Acquired resistance
- dc.subject.keyword Tyrosine kinase inhibitor
- dc.subject.keyword Cell lines
- dc.title Deep analysis of acquired resistance to FGFR1 inhibitor identifies MET and AKT activation and an expansion of AKT1 mutant cells
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion