A Functional Genetic Screen Identifies the Phosphoinositide 3-kinase Pathway as a Determinant of Resistance to Fibroblast Growth Factor Receptor Inhibitors in FGFR Mutant Urothelial Cell Carcinoma

Activating mutations and translocations of the FGFR3 gene are commonly seen in urothelial cell carcinoma (UCC) of the bladder and urinary tract. Several fibroblast growth factor receptor (FGFR) inhibitors are currently in clinical development and response rates appear promising for advanced UCC. A c...

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Published in:European urology Vol. 71; no. 6; pp. 858 - 862
Main Authors: Wang, Liqin, Šuštić, Tonći, Leite de Oliveira, Rodrigo, Lieftink, Cor, Halonen, Pasi, van de Ven, Marieke, Beijersbergen, Roderick L., van den Heuvel, Michel M., Bernards, René, van der Heijden, Michiel S.
Format: Journal Article
Language:English
Published: Switzerland Elsevier B.V 01.06.2017
Subjects:
Aminopyridines - pharmacology
Animals
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Benzamides - pharmacology
Bladder cancer
Carcinoma - drug therapy
Carcinoma - enzymology
Carcinoma - genetics
Carcinoma - pathology
Cell Line, Tumor
Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors
Class I Phosphatidylinositol 3-Kinases - genetics
Class I Phosphatidylinositol 3-Kinases - metabolism
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm - genetics
Drug Synergism
FGFR
Humans
Mice, Nude
Molecular Targeted Therapy
Morpholines - pharmacology
Mutation
PI3K
Piperazines - pharmacology
Protein Kinase Inhibitors - pharmacology
Pyrazoles - pharmacology
Receptors, Fibroblast Growth Factor - antagonists & inhibitors
Receptors, Fibroblast Growth Factor - genetics
Receptors, Fibroblast Growth Factor - metabolism
RNA Interference
Signal Transduction - drug effects
Synergy
Time Factors
Transfection
Tumor Burden - drug effects
Urinary Bladder Neoplasms - drug therapy
Urinary Bladder Neoplasms - enzymology
Urinary Bladder Neoplasms - genetics
Urinary Bladder Neoplasms - pathology
Urology
Urothelium - drug effects
Urothelium - enzymology
Urothelium - pathology
Xenograft Model Antitumor Assays
Synergy
PI3K
FGFR
Bladder cancer
ISSN:0302-2838, 1873-7560, 1873-7560
Online Access:Get full text
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Summary:Activating mutations and translocations of the FGFR3 gene are commonly seen in urothelial cell carcinoma (UCC) of the bladder and urinary tract. Several fibroblast growth factor receptor (FGFR) inhibitors are currently in clinical development and response rates appear promising for advanced UCC. A common problem with targeted therapeutics is intrinsic or acquired resistance of the cancer cells. To find potential drug targets that can act synergistically with FGFR inhibition, we performed a synthetic lethality screen for the FGFR inhibitor AZD4547 using a short hairpin RNA library targeting the human kinome in the UCC cell line RT112 (FGFR3-TACC3 translocation). We identified multiple members of the phosphoinositide 3-kinase (PI3K) pathway and found that inhibition of PIK3CA acts synergistically with FGFR inhibitors. The PI3K inhibitor BKM120 acted synergistically with inhibition of FGFR in multiple UCC and lung cancer cell lines having FGFR mutations. Consistently, we observed an elevated PI3K-protein kinase B pathway activity resulting from epidermal growth factor receptor or Erb-B2 receptor tyrosine kinase 3 reactivation caused by FGFR inhibition as the underlying molecular mechanism of the synergy. Our data show that feedback pathways activated by FGFR inhibition converge on the PI3K pathway. These findings provide a strong rationale to test FGFR inhibitors in combination with PI3K inhibitors in cancers harboring genetic activation of FGFR genes. Fibroblast growth factor receptor (FGFR) inhibitors are tested in bladder cancer patients. A genetic screen identified the phosphoinositide 3-kinase pathway to determine drug resistance. Combined treatment with FGFR and phosphoinositide 3-kinase inhibitors may improve response rates in patients with cancers harboring activating FGFR mutations
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ISSN:0302-2838
1873-7560
1873-7560
DOI:10.1016/j.eururo.2017.01.021