Functional screening of FGFR4-driven tumorigenesis identifies PI3K/mTOR inhibition as a therapeutic strategy in rhabdomyosarcoma.

Oncogene
Timothy McKinnonRebecca A Gladdy

Abstract

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and outcomes have stagnated, highlighting a need for novel therapies. Genomic analysis of RMS has revealed that alterations in the receptor tyrosine kinase (RTK)/RAS/PI3K axis are common and that FGFR4 is frequently mutated or overexpressed. Although FGFR4 is a potentially druggable receptor tyrosine kinase, its functions in RMS are undefined. This study tested FGFR4-activating mutations and overexpression for the ability to generate RMS in mice. Murine tumor models were subsequently used to discover potential therapeutic targets and to test a dual PI3K/mTOR inhibitor in a preclinical setting. Specifically, we provide the first mechanistic evidence of differential potency in the most common human RMS mutations, V550E or N535K, compared to FGFR4wt overexpression as murine myoblasts expressing FGFR4V550E undergo higher rates of cellular transformation, engraftment into mice, and rapidly form sarcomas that highly resemble human RMS. Murine tumor cells overexpressing FGFR4V550E were tested in an in vitro dose-response drug screen along with human RMS cell lines. Compounds were grouped by target class, and potency was determined using average percentage of area ...Continue Reading

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Citations

Jun 22, 2019·Pediatric Blood & Cancer·Marielle E YoheDavid M Langenau
Dec 8, 2019·Cancer Metastasis Reviews·Kerstin K Rauwolf, Claudia Rossig
Jul 7, 2019·Journal of Hematology & Oncology·Hui HuaYangfu Jiang
Mar 25, 2019·Cell Death and Differentiation·S Pauliina TurunenKaisa Lehti
Jan 29, 2020·Cancer Metastasis Reviews·Farah RamadanRaya Saab
Jan 19, 2021·Journal of Oncology·Demet Akdeniz OdemisHulya Yazici
Mar 7, 2021·Journal of Clinical Medicine·Christine M Heske, Leo Mascarenhas
May 1, 2021·Journal of Personalized Medicine·Antonio Juan RibellesAdela Cañete
Nov 14, 2020·International Journal of Molecular Sciences·Clara PerroneRossella Rota
May 14, 2021·Frontiers in Pharmacology·Yanan LiuHuanhai Xu

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Datasets Mentioned

BETA
GSE12102
GSE20196
GSE21050

Methods Mentioned

BETA
xenograft
PCR
SMA
transmission electron microscopy
fluorescence microscopy
transgenic

Clinical Trials Mentioned

NCT02567435

Software Mentioned

SPSS
GraphPad Prism
Helios

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