Reference Detail

Ref Type Journal Article
PMID (30140389)
Authors Gimenez-Xavier P, Pros E, Aza A, Moran S, Tonda R, Esteve-Codina A, Dabad M, Sanchez-Cespedes M
Title Deep analysis of acquired resistance to FGFR1 inhibitor identifies MET and AKT activation and an expansion of AKT1 mutant cells.
Journal Oncotarget
Vol 9
Issue 59
Date 2018 Jul 31
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
S266L missense no effect - predicted AKT1 S266L lies within the protein kinase domain of the Akt1 protein (UniProt.org). S266L has not been biochemically characterized, but is not transforming in cell culture and therefore, is predicted to have no effect on the Akt1 protein (PMID: 26701849), but has been associated with drug resistance in cultured cells (PMID: 30140389). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR1 amp lung cancer sensitive PD173074 Preclinical - Cell culture Actionable In a preclinical study, lung cancer cells harboring FGFR1 amplification were sensitive to PD173074 treatment in culture, demonstrating inhibition of cell growth (PMID: 30140389). 30140389
AKT1 S266L FGFR1 amp lung cancer predicted - sensitive Uprosertib Preclinical - Cell culture Actionable In a preclinical study, lung cancer cells harboring FGFR1 amplification and AKT1 S266L demonstrated sensitivity to Uprosertib (GSK2141795) in culture, showing decreased phosphorylation of Akt1 targets and reduced cell growth (PMID: 30140389). 30140389
AKT1 S266L FGFR1 amp lung cancer predicted - resistant PD173074 Preclinical - Cell culture Actionable In a preclinical study, lung cancer cells harboring FGFR1 amplification demonstrated resistance to increasing concentrations of PD173074 in culture and was subsequently, found to have acquired AKT1 S266L (PMID: 30140389). 30140389