Hedgehog-GLI signaling inhibition suppresses tumor growth in squamous lung cancer

Lingling Huang, Vonn Walter, D. Neil Hayes, Mark Onaitis

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

Purpose: Lung squamous cell carcinoma (LSCC) currently lacks effective targeted therapies. Previous studies reported overexpression of Hedgehog (HH)-GLI signaling components in LSCC. However, they addressed neither the tumor heterogeneity nor the requirement for HH-GLI signaling. Here, we investigated the role of HH-GLI signaling in LSCC, and studied the therapeutic potential of HH-GLI suppression. Experimental Design: Gene expression datasets of two independent LSCC patient cohorts were analyzed to study the activation of HH-GLI signaling. Four human LSCC cell lines were examined for HH-GLI signaling components. Cell proliferation and apoptosis were assayed in these cells after blocking the HH- GLI pathway by lentiviral-shRNA knockdown or small-molecule inhibitors. Xenografts in immunodeficient mice were used to determine the in vivo efficacy of GLI inhibitor GANT61. Results: In both cohorts, activation of HH-GLI signaling was significantly associated with the classical subtype of LSCC. In cell lines, genetic knockdown of Smoothened (SMO) produced minor effects on cell survival, whereas GLI2 knockdown significantly reduced proliferation and induced extensive apoptosis. Consistently, the SMO inhibitor GDC-0449 resulted in limited cytotoxicity in LSCC cells, whereas the GLI inhibitor GANT61 was very effective. Importantly, GANT61 demonstrated specific in vivo antitumor activity in xenograft models of GLI cell lines. Conclusion: Our studies demonstrate an important role for GLI2 in LSCC, and suggest GLI inhibition as a novel and potent strategy to treat a subset of patients with LSCC.

Original languageEnglish (US)
Pages (from-to)1566-1575
Number of pages10
JournalClinical Cancer Research
Volume20
Issue number6
DOIs
StatePublished - Jan 1 2014

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Hedgehogs
Squamous Cell Carcinoma
Lung Neoplasms
Lung
Growth
Neoplasms
HhAntag691
Heterografts
Cell Line
Apoptosis
Small Interfering RNA
Cell Survival
Research Design
Cell Proliferation
Gene Expression

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Huang, Lingling ; Walter, Vonn ; Hayes, D. Neil ; Onaitis, Mark. / Hedgehog-GLI signaling inhibition suppresses tumor growth in squamous lung cancer. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 6. pp. 1566-1575.
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Hedgehog-GLI signaling inhibition suppresses tumor growth in squamous lung cancer. / Huang, Lingling; Walter, Vonn; Hayes, D. Neil; Onaitis, Mark.

In: Clinical Cancer Research, Vol. 20, No. 6, 01.01.2014, p. 1566-1575.

Research output: Contribution to journalArticle

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