Epidermal growth factor receptor (EGFR) plays an important role in cancer progression. Several anti-EGFR mAbs has demonstrated significant clinical effect in the therapy of cancer. However, their impact on patients overall survival has been limited mainly by the emergence of different forms of tumor resistance. N-glycolyl variant of GM3 ganglioside (NGcGM3) has received some attention as a privileged target for cancer therapy. This ganglioside is specifically expressed in some tumors, and it has been associated with a poor prognostic in colon and lung cancer. Several reports in the literature have documented a functional relationship between GM3 and EGFR at tumor cell membrane. GM3 physically associates to EGFR inhibiting its ligand depend phosphorylation, but it also facilitates an alternative/compensatory signaling cascade mediated by Uroquinase Plasminogen Activator Receptor (uPAR) and integrin α5β1 interaction. However, no conclusive information exists on the difference between N-glycolyl and N-Acetyl variants of GM3 regarding their interaction with EGFR and uPAR. We hypothesized that the enrichment on NGcGM3 expression in some tumors relates to advantages of this ganglioside variant, perhaps by ensuring that both EGFR and uPAR pathways optimally signal to promote tumor growth and metastasis. Following this idea, we explored the impact of a combination of immunotherapies against this two “physically or functional related targets” in the tumor. We found a clear synergistic effect of this combination in two different transplantable tumor models of lung metastasis. We show that in treated metastasis, the combination turns off more the signaling through both EGFR and uPAR/α5β1 integrin pathway and both the antibody and cellular immune response induced was important. Overall, our results support the potential combination of therapies targeting NGcGM3 with anti EGFR antibodies to increase their efficacy in future clinical trials.

Citation Format: Addys Gonzalez, Rances Blanco, Adriana Carr, Kalet Leon. Synergistic potentiation of the anti-metastatic effect of anti EGFR mAbs by its combination with immunotherapies targeting the ganglioside NGcGM3 [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B120.