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.
Highlights
Type 1 insulin-like growth factor 1 receptor (IGFIR) signals via recruitment of adaptors, including insulin receptor substrate-1 (IRS-1) and Shc, to drive proliferation, invasion, and cell survival [1]
As detailed in Supplementary Methods, mice bearing DU145 xenografts were randomly allocated to 14 days treatment with 0.05-mL solvent (DMSO), 25 mg/kg AZ12253801 twice daily, 50 mg/kg DVL-PDZ inhibitor II (DVLi) once daily, or combination treatment
Forty-eight hours after siRNA transfection to allow target depletion, cells were treated with solvent or AZ12253801 at the GI50, and viability was assayed 5 days later
Summary
Type 1 insulin-like growth factor 1 receptor (IGFIR) signals via recruitment of adaptors, including insulin receptor substrate-1 (IRS-1) and Shc, to drive proliferation, invasion, and cell survival [1]. IGFIR inhibitory drugs induced objective regressions, some dramatic and durable, as monotherapy in Ewing sarcomas and other uncommon tumors, and with chemotherapy or targeted agents in common cancers [4,5,6,7,8,9]. These encouraging early reports have not translated to phase III benefit in unselected patients [10]. Key priorities are to understand what makes tumors resistant to IGFIR inhibition, use this information to target these drugs to potentially responsive patients, and select rational treatment combinations for clinical testing.
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