Abstract 733: A therapeutic opportunity in melanoma: Targeting CXCR1/2-dependent signaling attenuates therapy resistance

Abstract Advanced melanoma is one of the most intractable tumors, due to its insensitivity to all current treatment. Systemic chemotherapy is still considered the mainstay of treatment for advanced melanoma with limited survival impact. Failure of most agents is attributed to development of therapy resistance. Our previous findings demonstrate that CXCL-8 is a critical mediator in tumor growth, invasion, and angiogenesis. Two high affinity receptors for CXCL-8, CXCR1 and CXCR2, are differentially expressed on melanoma and endothelial cells. Based on these observations, we hypothesize that targeting CXCR1/2-dependent signaling will attenuate chemotherapy resistance and will synergistically enhance chemotherapeutic response for malignant melanoma. We used human melanoma cell lines A375P (low metastatic) and A375SM (highly metastatic), which express low and high levels of CXCL-8 respectively. First, we evaluated the role of CXCR1/2 ligands in chemo-resistance. CXCL-1 and -8 mRNA and protein expression was analyzed by quantitative realtime PCR and enzyme-linked immunosorbant assay, following treatment of dacarbazine and temozolomide. A significant increase in the CXCL-1 and -8 levels was observed in A375P and A375SM cells which was dependent on concentration and duration of chemotherapeutic treatment. In order to test whether blocking CXCR1/2 expression using genetic knock-down modulates chemotherapeutic responses, we used A375SM cells expressing different levels of CXCR1 and CXCR2. Our data suggest that knockdown of CXCR1 significantly enhanced the cytotoxic effect of dacarbazine in vitro. However, we did not observe a similar response in melanoma cells knocked down for CXCR2. Taken together, our preliminary data demonstrate that melanoma cells that survive chemotherapy express higher levels of CXCR1/2 ligands and targeting the CXCR1/2-dependent pathway might be a potential therapeutic approach to be combined with chemotherapy in advanced melanoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 733. doi:10.1158/1538-7445.AM2011-733