Platinum Priority – Brief Correspondence Editorial by XXX on pp. x–y of this issue 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 Liqin Wang a,y , Tonc ´i S ˇ usˇtic ´ a,y , Rodrigo Leite de Oliveira a,y , Cor Lieftink a , Pasi Halonen a , Marieke van de Ven b , Roderick L. Beijersbergen a , Michel M. van den Heuvel c , Rene ´ Bernards a, *, Michiel S. van der Heijden a,c, * a Division of Molecular Carcinogenesis, Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands; b Mouse Clinic Intervention Unit, The Netherlands Cancer Institute, Amsterdam, The Netherlands; c Division of Medical Oncology, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands E U R O P E A N U R O L O G Y X X X ( 2 0 1 6 ) X X X – X X X ava ilable at www.sciencedirect.com journa l homepage: www.europea nurology.com Article info Article history: Accepted January 6, 2017 Associate Editor: James Catto Keywords: FGFR Bladder cancer PI3K Synergy 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. # 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved. y These authors contributed equally. * Corresponding authors. Department of Medical Oncology, Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Tel. +31 20 512 6245; Fax: +31 20 512 2572 (M.S. van der Heijden); Department of Medical Oncology, Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amster- dam, The Netherlands. Tel. +31 20 512 1952 (R. Bernards). E-mail addresses: r.bernards@nki.nl (R. Bernards), ms.vd.heijden@nki.nl (M.S. van der Heijden). EURURO-7215; No. of Pages 5 Please cite this article in press as: Wang L, et al. 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. Eur Urol (2017), http://dx.doi.org/10.1016/j.eururo.2017.01.021 http://dx.doi.org/10.1016/j.eururo.2017.01.021 0302-2838/# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.