Drug synergy screen and network modeling in dedifferentiated liposarcoma identifies CDK4 and IGF1R as synergistic drug targets.

[dedifferentiated liposarcoma]

Dedifferentiated liposarcoma (DDLS ) is a rare but aggressive cancer with high recurrence and low response rates to targeted therapies . Increasing treatment efficacy may require combinations of targeted agents that counteract the effects of multiple abnormalities . To identify a possible multicomponent therapy , we performed a combinatorial drug screen in a DDLS -derived cell line and identified cyclin-dependent kinase 4 (CDK 4 ) and insulin-like growth factor 1 receptor (IGF 1 R ) as synergistic drug targets . We measured the phosphorylation of multiple proteins and cell viability in response to systematic drug combinations and derived computational models of the signaling network . These models predict that the observed synergy in reducing cell viability with CDK 4 and IGF 1 R inhibitors depends on the activity of the AKT pathway . Experiments confirmed that combined inhibition of CDK 4 and IGF 1 R cooperatively suppresses the activation of proteins within the AKT pathway . Consistent with these findings , synergistic reductions in cell viability were also found when combining CDK 4 inhibition with inhibition of either AKT or epidermal growth factor receptor (EGFR ), another receptor similar to IGF 1 R that activates AKT . Thus , network models derived from context-specific proteomic measurements of systematically perturbed cancer cells may reveal cancer -specific signaling mechanisms and aid in the design of effective combination therapies .

Diseases
Validation

Diseases presenting "identified cyclin-dependent kinase" symptom

dedifferentiated liposarcoma

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