title: 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.
abstract: 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.
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Liqin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Tonći
authors.initials: T
authors.lastname: Šuštić
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Leite de Oliveira
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Cor
authors.initials: C
authors.lastname: Lieftink
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Pasi
authors.initials: P
authors.lastname: Halonen
authors.affiliation: Mouse Clinic Intervention Unit, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: van de Ven
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Roderick L
authors.initials: RL
authors.lastname: Beijersbergen
authors.affiliation: Division of Medical Oncology, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: Michel M
authors.initials: MM
authors.lastname: van den Heuvel
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands. Electronic address: r.bernards@nki.nl.
authors.forename: René
authors.initials: R
authors.lastname: Bernards
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Division of Medical Oncology, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. Electronic address: ms.vd.heijden@nki.nl.
authors.forename: Michiel S
authors.initials: MS
authors.lastname: van der Heijden
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004357:Drug Synergism; D006801:Humans; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009025:Morpholines / Q000494:pharmacology*; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D034622:RNA Interference; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D019459:Urothelium / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: C572463:AZD4547; D000631:Aminopyridines; D001549:Benzamides; D009025:Morpholines; C571178:NVP-BKM120; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D017468:Receptors, Fibroblast Growth Factor; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human
keywords: Bladder cancer; FGFR; PI3K; Synergy