TY - JOUR
T1 - Inhibition of akt enhances the chemopreventive effects of topical rapamycin in mouse skin
AU - Dickinson, Sally E.
AU - Janda, Jaroslav
AU - Criswell, Jane
AU - Blohm-Mangone, Karen
AU - Olson, Erik R.
AU - Liu, Zhonglin
AU - Barber, Christy
AU - Petricoin, Emanuel F.
AU - Calvert, Valerie S.
AU - Einspahr, Janine
AU - Dickinson, Jesse E.
AU - Stratton, Steven P.
AU - Curiel-Lewandrowski, Clara
AU - Saboda, Kathylynn
AU - Hu, Chengcheng
AU - Bode, Ann M.
AU - Dong, Zigang
AU - Alberts, David S.
AU - Bowden, G. Timothy
N1 - Funding Information:
The authors thank PHusis Therapeutics Inc. for gift of the PHT-427 compound, Drs. Terry Landowski and Georg Wondrak for critical review of the manuscript, and Marlon Taylor and Nichole Burkett for sample processing. They also thank Jadrian Rusche for tireless efforts with technical support and tumor measurements; may he rest in peace. This work was supported by the following NIH grants: NCI P01 CA023074 (S.E. Dickinson, J. Janda, J. Criswell, K. Blohm-Mangone, E.R. Olson, J.J. Rusche, J. Einspahr, S.P. Stratton, C. Curiel-Lewandrowski, K. Saboda, C. Hu, A.M. Bode, Z. Dong, D. Alberts, G.T. Bowden), P30 CA027502 (all University of Arizona Cancer Center members) and NIBIB P41-EB002035 (C. Barber, Z. Liu). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
© 2016 American Association for Cancer Research.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2016/3
Y1 - 2016/3
N2 - The PI3Kinase/Akt/mTOR pathway has important roles in cancer development for multiple tumor types, including UV-induced nonmelanoma 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 with 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 with 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 with 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.
AB - The PI3Kinase/Akt/mTOR pathway has important roles in cancer development for multiple tumor types, including UV-induced nonmelanoma 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 with 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 with 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 with 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.
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U2 - 10.1158/1940-6207.CAPR-15-0419
DO - 10.1158/1940-6207.CAPR-15-0419
M3 - Article
C2 - 26801880
AN - SCOPUS:84962600117
SN - 1940-6207
VL - 9
SP - 215
EP - 224
JO - Cancer Prevention Research
JF - Cancer Prevention Research
IS - 3
ER -