1. Dsh homolog DVL3 mediates resistance to IGFIR inhibition by regulating IGF-RAS signaling.
- Author
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Gao S, Bajrami I, Verrill C, Kigozi A, Ouaret D, Aleksic T, Asher R, Han C, Allen P, Bailey D, Feller S, Kashima T, Athanasou N, Blay JY, Schmitz S, Machiels JP, Upile N, Jones TM, Thalmann G, Ashraf SQ, Wilding JL, Bodmer WF, Middleton MR, Ashworth A, Lord CJ, and Macaulay VM
- Subjects
- Animals, Antineoplastic Agents pharmacology, Carcinoma, Squamous Cell metabolism, Cell Line, Tumor, Dishevelled Proteins, Gene Expression, Head and Neck Neoplasms metabolism, Humans, Inhibitory Concentration 50, Isoxazoles pharmacology, MAP Kinase Signaling System, Male, Mice, Pyrimidines pharmacology, Receptor, IGF Type 1 metabolism, Wnt Proteins metabolism, Xenograft Model Antitumor Assays, Adaptor Proteins, Signal Transducing physiology, Drug Resistance, Neoplasm, Insulin-Like Growth Factor I physiology, Phosphoproteins physiology, Receptor, IGF Type 1 antagonists & inhibitors, ras Proteins metabolism
- 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., (©2014 American Association for Cancer Research.)
- Published
- 2014
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