buparlisib and Urinary-Bladder-Neoplasms

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.

Topics: Aminopyridines; Animals; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Carcinoma; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Synergism; Humans; Mice, Nude; Molecular Targeted Therapy; Morpholines; Mutation; Piperazines; Protein Kinase Inhibitors; Pyrazoles; Receptors, Fibroblast Growth Factor; RNA Interference; Signal Transduction; Time Factors; Transfection; Tumor Burden; Urinary Bladder Neoplasms; Urothelium; Xenograft Model Antitumor Assays