Article

Stage-dependent therapeutic efficacy in PI3K/mTOR-driven squamous cell carcinoma of the skin

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Abstract

Cutaneous squamous cell carcinoma (SCC) is a recurrent cancer that is prevalent in predisposed subjects such as immunosuppressed patients and patients being treated for other malignancies. Model systems to trial therapies at different stages of SCC development are lacking, therefore precluding efficient therapeutic interventions. Here, we have disrupted the expression of the tumor suppressor GRHL3 to induce loss of PTEN and activation of the PI3K/mTOR signaling pathway in mice and human skin, promoting aggressive SCC development. We then examined the potential for targeting PI3K/mTOR and an oncogenic driver miR-21, alone and in combination, for the prevention and treatment of SCC during the initiation, promotion/progression and establishment stages. Treatment with PI3K/mTOR inhibitors completely prevented tumor initiation, and these inhibitors significantly delayed the course of papilloma progression to malignancy. However, established SCC did not undergo any growth regression, indicating that this therapy is ineffective in established cancers. Mechanistically, the resistant SCCs displayed increased miR-21 expression in mice and humans where antagonists of miR-21 rescued expression levels of GRHL3/PTEN, but the combination of miR-21 antagonism with PI3K/mTOR inhibition resulted in acquired SCC resistance in part via c-MYC and OCT-4 upregulation. In conclusion, our data provide molecular evidence for the efficacy of targeting oncogenic drivers of SCC during the initiation and promotion stages and indicate that combination therapy may induce an aggressive phenotype when applied in the establishment stage.

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Acknowledgements

This study was supported by the Australian National Health and Medical Research (NHMRC, APP1049870, APP1106697). CD was supported by a fellowship from the Victorian Cancer Agency (Clare Oliver Memorial, COF11_04) and by a grant (11-0060) from The Association for International Cancer Research (AICR). RBP is supported by an NHMRC Research fellowship and CD is currently holding a Victorian Cancer Agency Mid-Career Fellowship (CR_16/5985). NVP-BEZ235 and NVP-BKM120 were obtained from Novartis (Basel, Switzerland). We thank Susan Jackson and Kerry Ardley for animal technical support and Dr Andrew Cuddihy for his critical reading and correction of the manuscript.

Author information

Author notes

  1. Edited by P. Bouillet

Affiliations

  1. Monash University Central Clinical School, Prahran, VIC, 3004, Australia

    • Charbel Darido
    • , Smitha R. Georgy
    • , Darren D. Partridge
    • , Seema Srivastava
    • , Marina R. Carpinelli
    •  & Stephen M. Jane
  2. Division of Cancer Research, Peter MacCallum Cancer Centre, Grattan Street, Parkville, VIC, 3052, Australia

    • Charbel Darido
    • , Carleen Cullinane
    • , Rachael Walker
    • , Suraya Roslan
    •  & Richard B. Pearson
  3. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, 3052, Australia

    • Charbel Darido
    • , Carleen Cullinane
    •  & Richard B. Pearson
  4. Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, VIC, 3010, Australia

    • Sebastian Dworkin
  5. Department of Physiology, Anatomy and Microbiology, LaTrobe University, Bundoora, VIC, 3086, Australia

    • Richard B. Pearson
  6. Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3168, Australia

    • Richard B. Pearson
  7. Department of Hematology, Alfred Hospital, Prahran, VIC, 3004, Australia

    • Stephen M. Jane

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The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Charbel Darido.

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