Dual Targeting of PDGFRα and FGFR1 Displays Synergistic Efficacy in Malignant Rhabdoid Tumors

Jocelyn P. Wong; Jason R. Todd; Martina A. Finetti; Frank McCarthy; Malgorzata Broncel; Simon Vyse; Maciej T. Luczynski; Stephen Crosier; Karen A. Ryall; Kate Holmes; Leo S. Payne; Frances Daley; Patty Wai; Andrew Jenks; Barbara Tanos; Aik-Choon Tan; Rachael C. Natrajan; Daniel Williamson; Paul H. Huang

doi:10.1016/j.celrep.2016.10.005

Dual Targeting of PDGFRα and FGFR1 Displays Synergistic Efficacy in Malignant Rhabdoid Tumors

Jocelyn P. Wong, Jason R. Todd, Martina A. Finetti, Frank McCarthy, Malgorzata Broncel, Simon Vyse, Maciej T. Luczynski, Stephen Crosier, Karen A. Ryall, Kate Holmes, Leo S. Payne, Frances Daley, Patty Wai, Andrew Jenks, Barbara Tanos, Aik-Choon Tan, Rachael C. Natrajan, Daniel Williamson, Paul H. Huang

Research output: Contribution to journal › Article

24 Citations (Scopus)

Abstract

Subunits of the SWI/SNF chromatin remodeling complex are mutated in a significant proportion of human cancers. Malignant rhabdoid tumors (MRTs) are lethal pediatric cancers characterized by a deficiency in the SWI/SNF subunit SMARCB1. Here, we employ an integrated molecular profiling and chemical biology approach to demonstrate that the receptor tyrosine kinases (RTKs) PDGFRα and FGFR1 are coactivated in MRT cells and that dual blockade of these receptors has synergistic efficacy. Inhibitor combinations targeting both receptors and the dual inhibitor ponatinib suppress the AKT and ERK1/2 pathways leading to apoptosis. MRT cells that have acquired resistance to the PDGFRα inhibitor pazopanib are susceptible to FGFR inhibitors. We show that PDGFRα levels are regulated by SMARCB1 expression, and assessment of clinical specimens documents the expression of both PDGFRα and FGFR1 in rhabdoid tumor patients. Our findings support a therapeutic approach in cancers with SWI/SNF deficiencies by exploiting RTK coactivation dependencies.

Original language	English
Pages (from-to)	1265-1275
Number of pages	11
Journal	Cell Reports
Volume	17
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2016.10.005
Publication status	Published - 2016 Oct 25
Externally published	Yes

Keywords

FGFR1
pazopanib
PDGFRα
receptor tyrosine kinase
rhabdoid tumor
signal transduction
SMARCB1
SWI/SNF
tyrosine kinase inhibitor

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.celrep.2016.10.005

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Wong, J. P., Todd, J. R., Finetti, M. A., McCarthy, F., Broncel, M., Vyse, S., Luczynski, M. T., Crosier, S., Ryall, K. A., Holmes, K., Payne, L. S., Daley, F., Wai, P., Jenks, A., Tanos, B., Tan, A-C., Natrajan, R. C., Williamson, D., & Huang, P. H. (2016). Dual Targeting of PDGFRα and FGFR1 Displays Synergistic Efficacy in Malignant Rhabdoid Tumors. Cell Reports, 17(5), 1265-1275. https://doi.org/10.1016/j.celrep.2016.10.005

Dual Targeting of PDGFRα and FGFR1 Displays Synergistic Efficacy in Malignant Rhabdoid Tumors. / Wong, Jocelyn P.; Todd, Jason R.; Finetti, Martina A.; McCarthy, Frank; Broncel, Malgorzata; Vyse, Simon; Luczynski, Maciej T.; Crosier, Stephen; Ryall, Karen A.; Holmes, Kate; Payne, Leo S.; Daley, Frances; Wai, Patty; Jenks, Andrew; Tanos, Barbara; Tan, Aik-Choon; Natrajan, Rachael C.; Williamson, Daniel; Huang, Paul H.

In: Cell Reports, Vol. 17, No. 5, 25.10.2016, p. 1265-1275.

Research output: Contribution to journal › Article

Wong, JP, Todd, JR, Finetti, MA, McCarthy, F, Broncel, M, Vyse, S, Luczynski, MT, Crosier, S, Ryall, KA, Holmes, K, Payne, LS, Daley, F, Wai, P, Jenks, A, Tanos, B, Tan, A-C, Natrajan, RC, Williamson, D & Huang, PH 2016, 'Dual Targeting of PDGFRα and FGFR1 Displays Synergistic Efficacy in Malignant Rhabdoid Tumors', Cell Reports, vol. 17, no. 5, pp. 1265-1275. https://doi.org/10.1016/j.celrep.2016.10.005

Wong, Jocelyn P. ; Todd, Jason R. ; Finetti, Martina A. ; McCarthy, Frank ; Broncel, Malgorzata ; Vyse, Simon ; Luczynski, Maciej T. ; Crosier, Stephen ; Ryall, Karen A. ; Holmes, Kate ; Payne, Leo S. ; Daley, Frances ; Wai, Patty ; Jenks, Andrew ; Tanos, Barbara ; Tan, Aik-Choon ; Natrajan, Rachael C. ; Williamson, Daniel ; Huang, Paul H. / Dual Targeting of PDGFRα and FGFR1 Displays Synergistic Efficacy in Malignant Rhabdoid Tumors. In: Cell Reports. 2016 ; Vol. 17, No. 5. pp. 1265-1275.

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AB - Subunits of the SWI/SNF chromatin remodeling complex are mutated in a significant proportion of human cancers. Malignant rhabdoid tumors (MRTs) are lethal pediatric cancers characterized by a deficiency in the SWI/SNF subunit SMARCB1. Here, we employ an integrated molecular profiling and chemical biology approach to demonstrate that the receptor tyrosine kinases (RTKs) PDGFRα and FGFR1 are coactivated in MRT cells and that dual blockade of these receptors has synergistic efficacy. Inhibitor combinations targeting both receptors and the dual inhibitor ponatinib suppress the AKT and ERK1/2 pathways leading to apoptosis. MRT cells that have acquired resistance to the PDGFRα inhibitor pazopanib are susceptible to FGFR inhibitors. We show that PDGFRα levels are regulated by SMARCB1 expression, and assessment of clinical specimens documents the expression of both PDGFRα and FGFR1 in rhabdoid tumor patients. Our findings support a therapeutic approach in cancers with SWI/SNF deficiencies by exploiting RTK coactivation dependencies.

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