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. Cancer Res; 74(20); 5866-77. Ó2014 AACR.

Suppression of homologous recombination sensitizes human tumor cells to IGF‐1R inhibition

“…Depletion of IGF‐1R itself did not affect AZ12253801 sensitivity (Fig. b ), consistent with findings that IGF‐1R expression has little predictive value for response to IGF‐1R inhibition . RAD51 depletion also inhibited cell viability, and induced ∼2‐fold reduction in AZ12253801 GI 50 (Figs.…”

“…RAD51 depletion also inhibited cell viability, and induced ∼2‐fold reduction in AZ12253801 GI 50 (Figs. c and d ), comparable to the siRNA screen results . We then tested three further prostate cancer cell lines, confirming RAD51 depletion by western blotting (Supporting Information Fig.…”

Phase I Dose-Escalation Study of Linsitinib (OSI-906) and Erlotinib in Patients with Advanced Solid Tumors

“…Functionally significant KRAS mutations were detected in 2 NSCLC patients, both of whom had SD, one durable. There are conflicting reports of the association of RAS mutation and/or RAS–MEK–ERK pathway activation with response to IGF1R inhibition, some (including the clinical R1507 study highlighted above) supporting association with sensitivity to IGF1R inhibition (44–46), and others with resistance (47, 48). EGFR mutations were detected in ctDNA of 3 of 30 NSCLC cases, consistent with the published incidence (10%–13%) of NSCLC EGFR mutations (49).…”

Combination therapy approaches to target insulin-like growth factor receptor signaling in breast cancer

“…Future studies investigating these types of dual therapies have merit; yet, the authors note that without sufficient biomarkers of efficacy, there will be many individuals who will not respond. Conversely, the WNT pathway element, DVL3, can potentially suppress the response of anti-IGF1R-targeted drugs via MEK-ERK regulation in cancer (Gao et al 2014). The study reports improved the clinical outcomes for individuals expressing low-absent DVL3 expression after figitumumab or AVE164 therapy and highlights that there is a need for positive and negative IGF1R therapy response biomarkers to be identified (Gao et al 2014).…”