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Therapeutics, Targets, and Chemical Biology

Dsh Homolog DVL3 Mediates Resistance to IGFIR Inhibition by Regulating IGF-RAS Signaling

Shan Gao, Ilirjana Bajrami, Clare Verrill, Asha Kigozi, Djamila Ouaret, Tamara Aleksic, Ruth Asher, Cheng Han, Paul Allen, Deborah Bailey, Stephan Feller, Takeshi Kashima, Nicholas Athanasou, Jean-Yves Blay, Sandra Schmitz, Jean-Pascal Machiels, Nav Upile, Terry M. Jones, George Thalmann, Shazad Q. Ashraf, Jennifer L. Wilding, Walter F. Bodmer, Mark R. Middleton, Alan Ashworth, Christopher J. Lord and Valentine M. Macaulay
Shan Gao
1Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
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Ilirjana Bajrami
2Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
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Clare Verrill
3Department of Cellular Pathology and NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, United Kingdom.
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Asha Kigozi
2Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
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Djamila Ouaret
1Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
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Tamara Aleksic
1Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
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Ruth Asher
3Department of Cellular Pathology and NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, United Kingdom.
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Cheng Han
1Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
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Paul Allen
4Department of Cellular Pathology, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, United Kingdom.
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Deborah Bailey
4Department of Cellular Pathology, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, United Kingdom.
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Stephan Feller
1Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
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Takeshi Kashima
1Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
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Nicholas Athanasou
5Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, Department of Pathology, Nuffield Orthopaedic Centre, Oxford, United Kingdom.
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Jean-Yves Blay
6University Claude Bernard Lyon I, Centre Léon Bérard, Department of Medicine, Lyon, France.
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Sandra Schmitz
7Service d'oncologie médicale, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
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Jean-Pascal Machiels
7Service d'oncologie médicale, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
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Nav Upile
8Liverpool CR-UK Centre, Department of Molecular and Clinical Cancer Medicine, Royal Liverpool University Hospital, Liverpool, United Kingdom.
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Terry M. Jones
8Liverpool CR-UK Centre, Department of Molecular and Clinical Cancer Medicine, Royal Liverpool University Hospital, Liverpool, United Kingdom.
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George Thalmann
9Department of Urology, Inselspital, Bern, Bern, Switzerland.
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Shazad Q. Ashraf
1Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
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Jennifer L. Wilding
1Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
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Walter F. Bodmer
1Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
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Mark R. Middleton
10Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, Liverpool, United Kingdom.
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Alan Ashworth
2Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
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Christopher J. Lord
2Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
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Valentine M. Macaulay
1Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
10Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, Liverpool, United Kingdom.
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  • For correspondence: valentine.macaulay@oncology.ox.ac.uk
DOI: 10.1158/0008-5472.CAN-14-0806 Published October 2014
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Abstract

Drugs that inhibit insulin-like growth factor 1 (IGFI) receptor IGFIR were encouraging in early trials, but predictive biomarkers were lacking and the drugs provided insufficient benefit in unselected patients. In this study, we used genetic screening and downstream validation to identify the WNT pathway element DVL3 as a mediator of resistance to IGFIR inhibition. Sensitivity to IGFIR inhibition was enhanced specifically in vitro and in vivo by genetic or pharmacologic blockade of DVL3. In breast and prostate cancer cells, sensitization tracked with enhanced MEK–ERK activation and relied upon MEK activity and DVL3 expression. Mechanistic investigations showed that DVL3 is present in an adaptor complex that links IGFIR to RAS, which includes Shc, growth factor receptor–bound-2 (Grb2), son-of-sevenless (SOS), and the tumor suppressor DAB2. Dual DVL and DAB2 blockade synergized in activating ERKs and sensitizing cells to IGFIR inhibition, suggesting a nonredundant role for DVL3 in the Shc–Grb2–SOS complex. Clinically, tumors that responded to IGFIR inhibition contained relatively lower levels of DVL3 protein than resistant tumors, and DVL3 levels in tumors correlated inversely with progression-free survival in patients treated with IGFIR antibodies. Because IGFIR does not contain activating mutations analogous to EGFR variants associated with response to EGFR inhibitors, we suggest that IGF signaling achieves an equivalent integration at the postreceptor level through adaptor protein complexes, influencing cellular dependence on the IGF axis and identifying a patient population with potential to benefit from IGFIR inhibition. Cancer Res; 74(20); 5866–77. ©2014 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • †Deceased.

  • Received March 20, 2014.
  • Revision received July 9, 2014.
  • Accepted July 27, 2014.
  • ©2014 American Association for Cancer Research.
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Cancer Research: 74 (20)
October 2014
Volume 74, Issue 20
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Dsh Homolog DVL3 Mediates Resistance to IGFIR Inhibition by Regulating IGF-RAS Signaling
Shan Gao, Ilirjana Bajrami, Clare Verrill, Asha Kigozi, Djamila Ouaret, Tamara Aleksic, Ruth Asher, Cheng Han, Paul Allen, Deborah Bailey, Stephan Feller, Takeshi Kashima, Nicholas Athanasou, Jean-Yves Blay, Sandra Schmitz, Jean-Pascal Machiels, Nav Upile, Terry M. Jones, George Thalmann, Shazad Q. Ashraf, Jennifer L. Wilding, Walter F. Bodmer, Mark R. Middleton, Alan Ashworth, Christopher J. Lord and Valentine M. Macaulay
Cancer Res October 15 2014 (74) (20) 5866-5877; DOI: 10.1158/0008-5472.CAN-14-0806

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Dsh Homolog DVL3 Mediates Resistance to IGFIR Inhibition by Regulating IGF-RAS Signaling
Shan Gao, Ilirjana Bajrami, Clare Verrill, Asha Kigozi, Djamila Ouaret, Tamara Aleksic, Ruth Asher, Cheng Han, Paul Allen, Deborah Bailey, Stephan Feller, Takeshi Kashima, Nicholas Athanasou, Jean-Yves Blay, Sandra Schmitz, Jean-Pascal Machiels, Nav Upile, Terry M. Jones, George Thalmann, Shazad Q. Ashraf, Jennifer L. Wilding, Walter F. Bodmer, Mark R. Middleton, Alan Ashworth, Christopher J. Lord and Valentine M. Macaulay
Cancer Res October 15 2014 (74) (20) 5866-5877; DOI: 10.1158/0008-5472.CAN-14-0806
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