Abstract 1081: Rapamycin is a chemopreventive and chemotherapeutic agent for ras-driven epidermal squamous cell carcinoma: evidence from mouse models.

Abstract Braf inhibitors are clinically important agents for the treatment of advanced melanoma however secondary cutaneous tumors are a common side effect; non-melanoma skin cancers (NMSCs) arise in 15-30% of patients on Braf inhibitor therapy and 60% of these harbor ras mutations. NMSC also occurs in 40% of organ transplant patients receiving immunosuppressive therapy, and switching from a calcineurin inhibitor-containing regimen to rapamycin reduces the incidence. To examine the effect of rapamycin on ras-driven epidermal squamous cell tumors, we treated mutant K-RasLA2 mice with rapamycin or vehicle by intraperitoneal injection and found that rapamycin prevented the development of squamous skin tumors (0/21 vs 6/24; p=0.04), and also rapidly reduced the tumor size. To explore this effect we employed a syngeneic orthotopic grafting model using H-Ras mutant primary murine keratinocytes to determine if rapamycin could hamper the ability of a Braf inhibitor to enhance squamous skin tumor growth. Similar to results in the K-RasLA2 model, rapamycin alone diminished the growth of tumors (size difference; 334.5 vs 22.3mm3; p=0.03), and decreased the volume even more in the presence of a Braf inhibitor (size difference; 699.6 vs 17.6 mm3; p=0.02). Treatment of established tumors with rapamycin resulted in significant tumor shrinkage even in the continuous presence of a Braf inhibitor. Size reduction was 78.7% and 66.7% in Braf inhibitor untreated and treated groups respectively. In vitro, Braf inhibition enhanced mutant H-Ras-induced activation of the Raf-ERK and mTOR pathways in keratinocytes, while rapamycin addition blocked the activation of signaling pathways and decreased cell proliferation. Taken together, rapamycin prevents murine skin tumor development arising from oncogenic mutations in two distinct types of ras gene alleles, and reduced the tumor size by inhibiting downstream oncogenic pathways. Rapamycin may have clinical application as a chemopreventive and therapeutic agent for patients at high risk to develop ras-driven NMSC, including those receiving Braf inhibitors. Citation Format: Hiroshi Kitagawa, Christophe Cataisson, Alessandra Handisurya, Patricia M. Day, Stuart H. Yuspa, Phillip A. Dennis. Rapamycin is a chemopreventive and chemotherapeutic agent for ras-driven epidermal squamous cell carcinoma: evidence from mouse models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1081. doi:10.1158/1538-7445.AM2013-1081