ROLES FOR EGFR AND IL-6 SIGNALING IN RHABDOMYOSARCOMA PATHOGENESIS
Valerie Granados, Pooja Dalal, Kathleen Galindo, Usha Avirneni, Rene Galindo.
The University of Texas Southwestern Medical Center, Dallas, TX.
Rhabdomyosarcoma (RMS) is a skeletal muscle-lineage sarcoma affecting children and adolescents that accounts for approximately 50% of all pediatric sarcoma cases. Clinical treatments for high-risk RMS haven't improved for 3 decades, arguing that new genetic tools and insights are needed to probe and target RMS. Using a signaling network uncovered in a forward genetic screen utilizing an RMS Drosophila model, we focus on evaluating the role of mis-regulated genetic networks in RMS pathobiology. One such pathway uncovered is the epidermal growth factor receptor (EGFR) pathway. In testing FDA-approved drugs that inhibit EGFR (e.g., Tarceva®) in RMS cell lines, we have found that Tarceva reduces RMS cell oncogenicity. Some RMS cell lines tested, however, show minimal to no response to Tarceva, suggesting the hypothesis that alternative/additional pathways facilitate RMS pathogenesis. Several prominent malignancies such as lung and prostate cancer have developed a mechanism to use both EGFR and IL-6 pathways to progress into a malignant phenotype, inducing proliferation, survival, and migration/invasion. We hypothesized that RMS exploits both EGFR and IL-6R pathways to enhance oncogenecity and questioned whether targeting EGFR and IL-6R in tandem would result in an additive/synergistic decrease in RMS pathogenesis. Preliminary results treating RMS cells with an anti-IL-6R monoclonal antibody (mAb) together with Tarceva demonstrates increased blockage of RMS oncogenicity than when treating with Tarceva or IL-6 mAb alone. Since humanized -IL-6R mAb (Tocilizumab®) is approved for clinical treatment of various diseases (e.g., rheumatoid arthritis, ovarian carcinoma), we anticipate Tarceva/IL-6 mAb combination therapy might represent a new avenue to clinically target RMS.