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Ref Type Journal Article
PMID (28108151)
Authors Wang L, Šuštić T, Leite de Oliveira R, Lieftink C, Halonen P, van de Ven M, Beijersbergen RL, van den Heuvel MM, Bernards R, van der Heijden MS
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.
Journal European urology
Vol 71
Issue 6
Date 2017 Jun
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR1 amp lung squamous cell carcinoma sensitive AZD4547 + Buparlisib Preclinical - Cell culture Actionable In a preclinical study, the combination of AZD4547 and Buparlisib (BKM120) induced apoptosis in a squamous cell lung cancer cell line with amplification of FGFR1 in culture (PMID: 28108151). 28108151
FGFR1 amp lung small cell carcinoma sensitive AZD4547 + Buparlisib Preclinical - Cell culture Actionable In a preclinical study, the combination of AZD4547 and Buparlisib (BKM120) induced apoptosis in a small cell lung cancer cell line with amplification of FGFR1 in culture (PMID: 28108151). 28108151
FGFR3 - TACC3 transitional cell carcinoma sensitive AZD4547 + Buparlisib Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of AZD4547 and Buparlisib (BKM120) worked synergistically to induce apoptosis and inhibit growth of a urothelial cell carcinoma cell line harboring FGFR3-TACC3 in culture, and inhibited tumor growth in xenograft models, with increased efficacy over either agent alone (PMID: 28108151). 28108151
FGFR1 amp transitional cell carcinoma sensitive AZD4547 + Buparlisib Preclinical - Cell culture Actionable In a preclinical study, the combination of AZD4547 and Buparlisib (BKM120) worked synergistically to induce apoptosis and inhibit growth of a urothelial cell carcinoma cell line with FGFR1 amplification in culture, with increased efficacy over either agent alone (PMID: 28108151). 28108151