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Cancer Drug Resist 2018;1:266-302 I http://dx.doi.org/10.20517/cdr.2018.18 Page 283

33. A FGF7-FGFR2 autocrine loop maintains fusion positive rhabdomyosarcoma cell growth
and is associated with preclinical efficacy of the FGFR inhibitor NVP-BGJ398

1
1
2
1
Christopher I. Milton , Joanna Selfe , Edoardo Missiaglia , Ewa Aladowicz , Zoë S. Walters , Su-
1
3
3
6
1
3
sanne A. Gatz , Melanie Generali , Gary Box , Melanie Valenti , Alexis de Haven-Brandon , Da-
4
5
4
5
vid Galiwango , Angela Hayes , Matthew Clarke , Elisa Izquierdo , David Gonzalez De Castro ,
6
1
4
Florence Raynaud , Suzanne Eccles , Janet M. Shipley
3
1 Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Insti-
tute of Cancer Research, London, UK
2 Department of Molecular Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne CH-1011, Switzer-
land
3 Tumour Biology and Metastasis Team, Division of Cancer Therapeutics, The Institute of Cancer Research,
London, UK
4 Drug Metabolism and Pharmacokinetics Team, Division of Cancer Therapeutics, The Institute of Cancer Re-
search, London, UK
5 Glioma Team, Division of Molecular Pathology, The Institute of Cancer Research, London, UK
6 Molecular Haematology, Division of Molecular Pathology, The Institute of Cancer Research, London, UK;
current address for Melanie Generali: Center for Therapy Development (GMP), Institute for Regenerative
Medicine (IREM), University of Zurich, Zurich CH-8044, Switzerland; and current address for David Gonza-
lez De Castro: School of Medicine, Dentistry and Biomedical sciences, Queens University Belfast, Belfast BT9
7BL, UK
Rhabdomyosarcoma (RMS) is the most common form of soft tissue sarcoma in children. Patients whose
tumours harbour a genetic fusion, the most common of which is PAX3-FOXO1, carry the worst prognosis
with a 5-year survival rate of less than 30%. Evidence demonstrates that fibroblast growth factor receptor
4 (FGFR4) plays a role in fusion positive RMS cell growth, although it is not clear whether other family
members (FGFRs 1-3) contribute as well. We sought to validate FGFR involvement in RMS proliferation
and to provide preclinical evidence that inhibiting FGFR signalling is a viable therapeutic strategy in this
tumour type. From a RMS cell line screen we identified fusion positive cells as more sensitive than fu-
sion negative cells to the FGFR inhibitor and clinical candidate NVP-BGJ398. Sensitivity correlated with
high mRNA expression of FGFR2 and its specific ligand FGF7. Genetic knockdown of FGF7 and FGFR2
decreased fusion positive but not fusion negative RMS cell viability. Interestingly, levels of secreted FGF7
protein were maintained alongside FGFR signalling through the MAPK pathway upon serum starvation.
This indicates that fusion positive RMS growth in vitro is sustained by a FGF7-FGFR2 autocrine loop. We
mined expression data from three independent RMS patient cohorts which revealed overexpression of
FGFR2 and FGF7 in fusion positive tumours compared to fusion negative tumours and normal muscle.
Oral administration of NVP-BGJ398 to immunodeficient mice, at doses within the range achievable in
humans, significantly inhibited fusion positive RMS01 and RH41 xenograft tumour growth, concomitant
with diminished FGFR/MAPK signalling and a lower proliferative index. Finally, using clonogenic assays
in vitro we demonstrate that NVP-BGJ398 is synergistic in combination with Irinotecan, a chemotherapeu-
tic used in the standard treatment of RMS patients. Together these data suggest that NVP-BGJ398 is an at-
tractive therapeutic option, particularly in combination with Irinotecan, for high-risk fusion positive RMS
patients.

34. Exploring resistance of renal cell carcinoma to targeted therapy

1,2
3
Hossam M. Kamli , Li Li , David A. Vesey , Glenda C. Gobe 1,5
1,4
1 University of Queensland Princess Alexandra Hospital Kidney Disease Research Collaborative, Translational
Research Institute, Brisbane, Queensland, Australia