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

Oncotarget
Pol Gimenez-XavierMontse Sanchez-Cespedes

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.

References

Jul 10, 2007·Bioorganic & Medicinal Chemistry Letters·Naparat KammasudOpa Vajragupta
Dec 14, 2007·Proceedings of the National Academy of Sciences of the United States of America·Ultan McDermottJeffrey Settleman
Nov 1, 2008·Molecular Cancer Therapeutics·Thomas Bachleitner-HofmannMartin R Weiser
Jan 16, 2009·Biochemical Society Transactions·Jingxiang Huang, Brendan D Manning
May 28, 2009·Human Mutation·Raquel BlancoMontse Sanchez-Cespedes
Mar 4, 2011·Trends in Molecular Medicine·Heidi Greulich, Pamela M Pollock
Mar 25, 2011·Science Translational Medicine·Lecia V SequistJeffrey A Engelman
Apr 20, 2011·Proceedings of the National Academy of Sciences of the United States of America·Ryohei KatayamaAlice T Shaw
Jan 27, 2012·Science Translational Medicine·Ryohei KatayamaJeffrey A Engelman
Jul 4, 2012·Nature Genetics·Zhenfeng ZhangTrever G Bivona
Oct 20, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jingchuan ZhangPaul R Gavine
Feb 13, 2013·International Journal of Cancer. Journal International Du Cancer·Eva ProsMontse Sanchez-Cespedes
Feb 13, 2013·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Alice T Shaw, Jeffrey A Engelman
Jul 2, 2014·Nature Reviews. Clinical Oncology·D Ross CamidgeLecia V Sequist
Mar 4, 2017·Molecular Cancer Therapeutics·Jharna DattaSameek Roychowdhury
Apr 12, 2017·Molecular Cancer Therapeutics·Pol Gimenez-XavierMontse Sanchez-Cespedes
Jun 21, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Florian MalchersRoman K Thomas

❮ Previous
Next ❯

Datasets Mentioned

BETA
GSE115777

Methods Mentioned

BETA
RNA-seq
methylation profiling
PCR
electrophoresis

Software Mentioned

Integrative Genomics Viewer ( IGV )
GEM
Gene Set Enrichment Analysis ( GSEA
Prism
GraphPad
GSEA

Related Concepts

Related Feeds

AKT Pathway

This feed focuses on the AKT serine/threonine kinase, which is an important signaling pathway involved in processes such as glucose metabolism and cell survival.