Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
European urology	71	6	2017 Jun	858-862	Eur Urol

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	Buparlisib + Fexagratinib	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	transitional cell carcinoma	sensitive	Buparlisib + Fexagratinib	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
FGFR1 amp	lung small cell carcinoma	sensitive	Buparlisib + Fexagratinib	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