Inhibition of Akt Enhances the Chemopreventive Effects of Topical Rapamycin in Mouse Skin

Abstract

The PI3Kinase/Akt/mTOR pathway has important roles in cancer development for multiple tumor types, including UV-induced non-melanoma skin cancer. Immunosuppressed populations are at increased risk of aggressive cutaneous squamous cell carcinoma (SCC). Individuals who are treated with rapamycin, (sirolimus, a classical mTOR inhibitor) have significantly decreased rates of developing new cutaneous SCCs compared to those that receive traditional immunosuppression. However, systemic rapamycin use can lead to significant adverse events. Here we explored the use of topical rapamycin as a chemopreventive agent in the context of solar simulated light (SSL)-induced skin carcinogenesis. In SKH-1 mice, topical rapamycin treatment decreased tumor yields when applied after completion of 15 weeks of SSL exposure compared to controls. However, applying rapamycin during SSL exposure for 15 weeks, and continuing for 10 weeks after UV treatment, increased tumor yields. We also examined whether a combinatorial approach might result in more significant tumor suppression by rapamycin. We validated that rapamycin causes increased Akt (S473) phosphorylation in the epidermis after SSL, and show for the first time that this dysregulation can be inhibited in vivo by a selective PDK1/Akt inhibitor, PHT-427. Combining rapamycin with PHT-427 on tumor prone skin additively caused a significant reduction of tumor multiplicity compared to vehicle controls. Our findings indicate that patients taking rapamycin should avoid sun exposure, and that combining topical mTOR inhibitors and Akt inhibitors may be a viable chemoprevention option for individuals at high risk for cutaneous SCC.

Resatorvid‐based Pharmacological Antagonism of Cutaneous TLR4 Blocks UV‐induced NF‐κB and AP‐1 Signaling in Keratinocytes and Mouse Skin

“…We then examined the effect of pharmacological inhibition of TLR4 on UVinduced MAP kinase signaling employing solar-simulated light (SSL). SSL uses a light source which replicates the relative contributions of UVA and UVB found in natural sunlight, as previously published (3,37). We observed that stimulation of p38 MAP kinase phosphorylation in response to SSL was attenuated in the presence of resatorvid (Fig.…”

“…For in vivo exposures, a bank of 6 UVA340 bulbs was utilized within an approved ventilated animal rack. Fluence intensity for both types of bulbs was measured as described previously .…”

Cutaneous Squamous Cell Carcinoma: From Biology to Therapy

“…mTOR inhibitors such as rapamycin are currently being used to decrease the risk of CSCC development in immunosuppressed patients that receive traditional immunosuppression [95][96][97]. Combining topical mTOR inhibitors and AKT inhibitors (PHT-427) enhances the chemopreventive effects of rapamycin [98]. Pan-PI3K and selective PI3K inhibitors have been developed to treat other cancers [99].…”

Molecular signaling cascades involved in nonmelanoma skin carcinogenesis

“…In addition, organ-transplant patients who took rapamycin as an immunosuppressive drug had a significant reduction in acquired NMSC when compared to patients taking cyclosporine A [164]. Our lab and others have demonstrated that mTORC1 is required for keratinocyte hyperproliferation in response to tumor promotion in murine skin carcinogenesis models [129, 165]. There is controversy regarding the role of mTORC1 in NMSC tumor initiation.…”

“…Studies from our lab showed that treatment with rapamycin or genetic knockdown of the essential mTORC1 scaffolding protein Raptor does not affect cell viability or apoptosis following exposure to UVB in spontaneously immortalized human keratinocytes (HaCaT cells) or mouse primary keratinocytes [129, 145]. In contrast, a recent report by Bowden and colleagues showed that rapamycin treatment did increase UVR-induced keratinocyte cell death in mice [165]. The differing results seen in these studies are likely due to the differences in both model systems and UVR-dosages used.…”