Inhibition of akt enhances the chemopreventive effects of topical rapamycin in mouse skin

Sally E Dickinson, Jaroslav Janda, Jane Criswell, Karen Blohm-Mangone, Erik R. Olson, Zhonglin Liu, Christy Barber, Emanuel F. Petricoin, Valerie S. Calvert, Janine G Einspahr, Jesse E. Dickinson, Steven P Stratton, Clara N Curiel, Kathylynn Saboda, Chengcheng Hu, Ann M. Bode, Zigang Dong, David S Alberts, G. Timothy Bowden

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)215-224
Number of pages10
JournalCancer Prevention Research
Volume9
Issue number3
DOIs
StatePublished - Mar 1 2016

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Sirolimus
Skin
Neoplasms
Light
Squamous Cell Carcinoma
Chemoprevention
Skin Neoplasms
Solar System
Epidermis
Immunosuppression
Carcinogenesis
Phosphorylation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Inhibition of akt enhances the chemopreventive effects of topical rapamycin in mouse skin. / Dickinson, Sally E; Janda, Jaroslav; Criswell, Jane; Blohm-Mangone, Karen; Olson, Erik R.; Liu, Zhonglin; Barber, Christy; Petricoin, Emanuel F.; Calvert, Valerie S.; Einspahr, Janine G; Dickinson, Jesse E.; Stratton, Steven P; Curiel, Clara N; Saboda, Kathylynn; Hu, Chengcheng; Bode, Ann M.; Dong, Zigang; Alberts, David S; Bowden, G. Timothy.

In: Cancer Prevention Research, Vol. 9, No. 3, 01.03.2016, p. 215-224.

Research output: Contribution to journalArticle

Dickinson, SE, Janda, J, Criswell, J, Blohm-Mangone, K, Olson, ER, Liu, Z, Barber, C, Petricoin, EF, Calvert, VS, Einspahr, JG, Dickinson, JE, Stratton, SP, Curiel, CN, Saboda, K, Hu, C, Bode, AM, Dong, Z, Alberts, DS & Bowden, GT 2016, 'Inhibition of akt enhances the chemopreventive effects of topical rapamycin in mouse skin', Cancer Prevention Research, vol. 9, no. 3, pp. 215-224. https://doi.org/10.1158/1940-6207.CAPR-15-0419
Dickinson, Sally E ; Janda, Jaroslav ; Criswell, Jane ; Blohm-Mangone, Karen ; Olson, Erik R. ; Liu, Zhonglin ; Barber, Christy ; Petricoin, Emanuel F. ; Calvert, Valerie S. ; Einspahr, Janine G ; Dickinson, Jesse E. ; Stratton, Steven P ; Curiel, Clara N ; Saboda, Kathylynn ; Hu, Chengcheng ; Bode, Ann M. ; Dong, Zigang ; Alberts, David S ; Bowden, G. Timothy. / Inhibition of akt enhances the chemopreventive effects of topical rapamycin in mouse skin. In: Cancer Prevention Research. 2016 ; Vol. 9, No. 3. pp. 215-224.
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