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 › peer-review

43 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

Bibliographical note

Funding Information:
This work was supported by grants from the Institute of Cancer Research (ICR) , Cancer Research UK ( C36478/A19281 ), Sarcoma UK ( 003.2014 ), Royal Marsden Cancer Charity , and Biotechnology and Biological Sciences Research Council (BBSRC) ( BB/I014276/I and BB/M013782/1 ) to P.H.H.; Breast Cancer Now ( SF01May2011 ) to R.C.N.; NIH ( T32CA17468 ) to K.A.R.; David F. and Margaret T. Grohne Family Foundation to A.-C.T.; and Children With Cancer UK ( 2012/134 ), North Eastern Children’s Cancer Research (NECCR) (NCC Core Grant Support) to D.W., whose work was undertaken within the remit of a Children’s Cancer and Leukaemia Group (CCLG) Biological Study 2012 BS 05 and as part of the INSTINCT network programme grant, co-funded by The Brain Tumour Charity , Great Ormond Street Children’s Charity , and Children With Cancer UK ( 16/193 ). The CHLA226 and BT12 cell lines were kindly provided by the Children’s Oncology Group Cell Culture Repository.

Publisher Copyright:
© 2016 The Author(s)

Keywords

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

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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

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, AC, 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

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title = "Dual Targeting of PDGFRα and FGFR1 Displays Synergistic Efficacy in Malignant Rhabdoid Tumors",

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.",

keywords = "FGFR1, PDGFRα, SMARCB1, SWI/SNF, pazopanib, receptor tyrosine kinase, rhabdoid tumor, signal transduction, tyrosine kinase inhibitor",

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

note = "Funding Information: This work was supported by grants from the Institute of Cancer Research (ICR) , Cancer Research UK ( C36478/A19281 ), Sarcoma UK ( 003.2014 ), Royal Marsden Cancer Charity , and Biotechnology and Biological Sciences Research Council (BBSRC) ( BB/I014276/I and BB/M013782/1 ) to P.H.H.; Breast Cancer Now ( SF01May2011 ) to R.C.N.; NIH ( T32CA17468 ) to K.A.R.; David F. and Margaret T. Grohne Family Foundation to A.-C.T.; and Children With Cancer UK ( 2012/134 ), North Eastern Children{\textquoteright}s Cancer Research (NECCR) (NCC Core Grant Support) to D.W., whose work was undertaken within the remit of a Children{\textquoteright}s Cancer and Leukaemia Group (CCLG) Biological Study 2012 BS 05 and as part of the INSTINCT network programme grant, co-funded by The Brain Tumour Charity , Great Ormond Street Children{\textquoteright}s Charity , and Children With Cancer UK ( 16/193 ). The CHLA226 and BT12 cell lines were kindly provided by the Children{\textquoteright}s Oncology Group Cell Culture Repository. Publisher Copyright: {\textcopyright} 2016 The Author(s)",

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doi = "10.1016/j.celrep.2016.10.005",

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AU - Wong, Jocelyn P.

AU - Todd, Jason R.

AU - Finetti, Martina A.

AU - McCarthy, Frank

AU - Broncel, Malgorzata

AU - Vyse, Simon

AU - Luczynski, Maciej T.

AU - Crosier, Stephen

AU - Ryall, Karen A.

AU - Holmes, Kate

AU - Payne, Leo S.

AU - Daley, Frances

AU - Wai, Patty

AU - Jenks, Andrew

AU - Tanos, Barbara

AU - Tan, Aik Choon

AU - Natrajan, Rachael C.

AU - Williamson, Daniel

AU - Huang, Paul H.

N1 - Funding Information: This work was supported by grants from the Institute of Cancer Research (ICR) , Cancer Research UK ( C36478/A19281 ), Sarcoma UK ( 003.2014 ), Royal Marsden Cancer Charity , and Biotechnology and Biological Sciences Research Council (BBSRC) ( BB/I014276/I and BB/M013782/1 ) to P.H.H.; Breast Cancer Now ( SF01May2011 ) to R.C.N.; NIH ( T32CA17468 ) to K.A.R.; David F. and Margaret T. Grohne Family Foundation to A.-C.T.; and Children With Cancer UK ( 2012/134 ), North Eastern Children’s Cancer Research (NECCR) (NCC Core Grant Support) to D.W., whose work was undertaken within the remit of a Children’s Cancer and Leukaemia Group (CCLG) Biological Study 2012 BS 05 and as part of the INSTINCT network programme grant, co-funded by The Brain Tumour Charity , Great Ormond Street Children’s Charity , and Children With Cancer UK ( 16/193 ). The CHLA226 and BT12 cell lines were kindly provided by the Children’s Oncology Group Cell Culture Repository. Publisher Copyright: © 2016 The Author(s)

PY - 2016/10/25

Y1 - 2016/10/25

N2 - 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.

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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KW - receptor tyrosine kinase

KW - rhabdoid tumor

KW - signal transduction

KW - tyrosine kinase inhibitor

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SN - 2211-1247

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ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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