title: Dsh homolog DVL3 mediates resistance to IGFIR inhibition by regulating IGF-RAS signaling.
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.
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Shan
authors.initials: S
authors.lastname: Gao
authors.affiliation: Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Ilirjana
authors.initials: I
authors.lastname: Bajrami
authors.affiliation: Department of Cellular Pathology and NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Clare
authors.initials: C
authors.lastname: Verrill
authors.affiliation: Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Asha
authors.initials: A
authors.lastname: Kigozi
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Djamila
authors.initials: D
authors.lastname: Ouaret
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Tamara
authors.initials: T
authors.lastname: Aleksic
authors.affiliation: Department of Cellular Pathology and NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Asher
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Cheng
authors.initials: C
authors.lastname: Han
authors.affiliation: Department of Cellular Pathology, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Allen
authors.affiliation: Department of Cellular Pathology, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Deborah
authors.initials: D
authors.lastname: Bailey
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Stephan
authors.initials: S
authors.lastname: Feller
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kashima
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, Department of Pathology, Nuffield Orthopaedic Centre, Oxford, United Kingdom.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Athanasou
authors.affiliation: University Claude Bernard Lyon I, Centre Léon Bérard, Department of Medicine, Lyon, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
authors.affiliation: Service d'oncologie médicale, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: Schmitz
authors.affiliation: Service d'oncologie médicale, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Jean-Pascal
authors.initials: JP
authors.lastname: Machiels
authors.affiliation: Liverpool CR-UK Centre, Department of Molecular and Clinical Cancer Medicine, Royal Liverpool University Hospital, Liverpool, United Kingdom.
authors.forename: Nav
authors.initials: N
authors.lastname: Upile
authors.affiliation: Liverpool CR-UK Centre, Department of Molecular and Clinical Cancer Medicine, Royal Liverpool University Hospital, Liverpool, United Kingdom.
authors.forename: Terry M
authors.initials: TM
authors.lastname: Jones
authors.affiliation: Department of Urology, Inselspital, Bern, Bern, Switzerland.
authors.forename: George
authors.initials: G
authors.lastname: Thalmann
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Shazad Q
authors.initials: SQ
authors.lastname: Ashraf
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Wilding
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Walter F
authors.initials: WF
authors.lastname: Bodmer
authors.affiliation: Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, Liverpool, United Kingdom.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Middleton
authors.affiliation: Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.affiliation: Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom. Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, Liverpool, United Kingdom. valentine.macaulay@oncology.ox.ac.uk.
authors.forename: Valentine M
authors.initials: VM
authors.lastname: Macaulay
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D045744:Cell Line, Tumor; D000072261:Dishevelled Proteins; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D006258:Head and Neck Neoplasms / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D007555:Isoxazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D010750:Phosphoproteins / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C562081:AZ 12253801; D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; C000606584:DVL3 protein, human; D000072261:Dishevelled Proteins; C000606585:Dvl3 protein, mouse; C583557:IGF1 protein, human; D007555:Isoxazoles; D010750:Phosphoproteins; D011743:Pyrimidines; D051153:Wnt Proteins; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D018631:ras Proteins