Drug Synergy Screen and Network Modeling in Dedifferentiated Liposarcoma Identifies CDK4 and IGF1R as Synergistic Drug Targets

Abstract

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 (CDK4) and insulin-like growth factor 1 receptor (IGF1R) 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 CDK4 and IGF1R inhibitors depend on activity of the AKT pathway. Experiments confirmed that combined inhibition of CDK4 and IGF1R cooperatively suppresses the activation of proteins within the AKT pathway. Consistent with these findings, synergistic reductions in cell viability were also found when combining CDK4 inhibition with inhibition of either AKT or epidermal growth factor receptor (EGFR), another receptor similar to IGF1R 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.

CDK4 is an essential insulin effector in adipocytes

“…IRS proteins transduce mitogenic, antiapoptotic, and antidifferentiation signals to the cell, mainly through the PI3K-AKT module (28). Although antioncogenic synergistic effects have been observed using either CDK4 and IGF1R inhibitors or CDK4 and PI3K inhibitors, no crosstalk between both pathways has been described (29)(30)(31)(32). The CDK4/ CDK6 inhibitor (PD0332991, palbociclib) has been approved for the treatment of breast cancer (33).…”

Antiproliferative Effects of CDK4/6 Inhibition inCDK4-Amplified Human LiposarcomaIn VitroandIn Vivo

“…Barretina and colleagues showed cell-cycle arrest and growth inhibition in two liposarcoma cell lines treated with CDK4 shRNA or the CDK4/6 inhibitor PD0332991 (19). A more recent study also reported that the addition of an IGF1R inhibitor to PD0332991 led to greater inhibition of cell-cycle progression and cell metabolic activity (20). However, detailed biochemical analyses and the preclinical in vivo effects of CDK4/6 inhibitors on liposarcoma xenograft models have not yet been described, and predictive biomarkers for CDK4/6 inhibitor activity are still lacking.…”

Quantification of Pathway Cross-talk Reveals Novel Synergistic Drug Combinations for Breast Cancer

“…These numbers emphasize the significant enrichment of synergistic drug combinations compared with traditional experimental high-throughput screens (P < 1eÀ04; Supplementary Fig. S8A and S8B), which detect synergy in 4% to 14% of the drug pairs tested (16,34,35). A detailed description of the comparison can be found in the Supplementary Material (Section S6).…”

“…In addition, we assessed the PCI for 68 synergistic, additive, or antagonistic drug pairs identified in a combination screen performed in a tumor-derived liposarcoma cell line (DDLS817) considering 14 targeted compounds from distinct drug classes (16). This screen resulted in 14.3% synergistic, 38.5% additive, and 22% antagonistic combinations.…”

“…Different approaches are available for predicting drug combinations for complex diseases, mostly including mathematical modeling, stochastic search techniques, as well as cell contextbased methods like global gene expression or targeted phosphoproteomics profiling (10)(11)(12)(13). More recently, network-based models have been proposed for identifying drug synergies and for examining the mechanisms of action of efficient combinations (14)(15)(16).…”