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Mol Cancer Ther. 2017 Apr;16(4):614-624. doi: 10.1158/1535-7163.MCT-15-1010. Epub 2017 Mar 2.

Akt Activation Mediates Acquired Resistance to Fibroblast Growth Factor Receptor Inhibitor BGJ398.

Author information

1
Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
2
Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
3
Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio.
4
Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio. sameek.roychowdhury@osumc.edu.
5
Department of Pharmacology, The Ohio State University, Columbus, Ohio.

Abstract

Activation of FGFR signaling through mutations, amplifications, or fusions involving FGFR1, 2, 3, or 4 is seen in multiple tumors, including lung, bladder, and cholangiocarcinoma. Currently, several clinical trials are evaluating the role of novel FGFR inhibitors in solid tumors. As we move forward with FGFR inhibitors clinically, we anticipate the emergence of resistance with treatment. Consequently, we sought to study the mechanism(s) of acquired resistance to FGFR inhibitors using annotated cancer cell lines. We identified cancer cell lines that have activating mutations in FGFR1, 2, or 3 and treated them chronically with the selective FGFR inhibitor, BGJ398. We observed resistance to chronic BGJ398 exposure in DMS114 (small-cell lung cancer, FGFR1 amplification) and RT112 (urothelial carcinoma, FGFR3 fusion/amplification) cell lines based on viability assays. Reverse-phase protein array (RPPA) analysis showed increased phosphorylation of Akt (T308 and S473) and its downstream target GSK3 (S9 and S21) in both the resistant cell lines when compared with matching controls. Results of RPPA were confirmed using immunoblots. Consequently, the addition of an Akt inhibitor (GSK2141795) or siRNA was able to restore sensitivity to BGJ398 in resistant cell lines. These data suggest a role for Akt pathway in mediating acquired resistance to FGFR inhibition. Mol Cancer Ther; 16(4); 614-24. ©2017 AACR.

PMID:
28255027
PMCID:
PMC5539948
DOI:
10.1158/1535-7163.MCT-15-1010
[Indexed for MEDLINE]
Free PMC Article

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