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

Charbel Darido, Smitha R. Georgy, Carleen Cullinane, Darren D. Partridge, Rachael Walker, Seema Srivastava, Suraya Roslan, Marina R. Carpinelli, Sebastian Dworkin, Richard B. Pearson, Stephen M. Jane

Research output: Contribution to journalArticleResearchpeer-review

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1146-1159
Number of pages14
JournalCell Death and Differentiation
Volume25
Issue number6
DOIs
Publication statusPublished - 1 Jun 2018

Cite this

@article{d591d1db186441e982cacbfd0c5b76da,
title = "Stage-dependent therapeutic efficacy in PI3K/mTOR-driven squamous cell carcinoma of the skin",
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.",
author = "Charbel Darido and Georgy, {Smitha R.} and Carleen Cullinane and Partridge, {Darren D.} and Rachael Walker and Seema Srivastava and Suraya Roslan and Carpinelli, {Marina R.} and Sebastian Dworkin and Pearson, {Richard B.} and Jane, {Stephen M.}",
year = "2018",
month = "6",
day = "1",
doi = "10.1038/s41418-017-0032-0",
language = "English",
volume = "25",
pages = "1146--1159",
journal = "Cell Death and Differentiation",
issn = "1350-9047",
publisher = "Nature Publishing Group",
number = "6",

}

Stage-dependent therapeutic efficacy in PI3K/mTOR-driven squamous cell carcinoma of the skin. / Darido, Charbel; Georgy, Smitha R.; Cullinane, Carleen; Partridge, Darren D.; Walker, Rachael; Srivastava, Seema; Roslan, Suraya; Carpinelli, Marina R.; Dworkin, Sebastian; Pearson, Richard B.; Jane, Stephen M.

In: Cell Death and Differentiation, Vol. 25, No. 6, 01.06.2018, p. 1146-1159.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Stage-dependent therapeutic efficacy in PI3K/mTOR-driven squamous cell carcinoma of the skin

AU - Darido, Charbel

AU - Georgy, Smitha R.

AU - Cullinane, Carleen

AU - Partridge, Darren D.

AU - Walker, Rachael

AU - Srivastava, Seema

AU - Roslan, Suraya

AU - Carpinelli, Marina R.

AU - Dworkin, Sebastian

AU - Pearson, Richard B.

AU - Jane, Stephen M.

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85038037474&partnerID=8YFLogxK

U2 - 10.1038/s41418-017-0032-0

DO - 10.1038/s41418-017-0032-0

M3 - Article

VL - 25

SP - 1146

EP - 1159

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

SN - 1350-9047

IS - 6

ER -