GLI1 blockade potentiates the antitumor activity of PI3K antagonists in lung squamous cell carcinoma

Sahba Kasiri, Chunli Shao, Baozhi Chen, Alexandra N. Wilson, Paul Yenerall, Brenda C. Timmons, Luc Girard, Hui Tian, Carmen Behrens, Ignacio I. Wistuba, Adi F. Gazdar, James Kim

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Lung squamous cell carcinoma (SCC), strongly associated with smoking, is treated primarily with traditional cytotoxic chemotherapy due to a lack of FDA-approved targeted agents available. Here, we identify the Hedgehog pathway transcription factor GLI1 as a critical driver of lung SCC. Analysis of human lung cancer datasets showed that GLI1 mRNA was highly expressed in human lung SCC and portended a poor prognosis. Inhibition of GLI1 in human lung SCC cell lines suppressed tumor cell clonogenicity and proliferation in culture and in vivo. Addition of SHH ligand, SMO antagonists, or other Hedgehog pathway agonists did not affect GLI1 expression in lung SCC cells. However, GLI1 expression was modulated by either inhibition or activation of the PI3K and MAPK pathways. Furthermore, in vivo growth of SCC harboring amplifications of the PI3K gene PIK3CA was attenuated by antagonizing GLI1 and PI3K. Thus, a combinatorial therapeutic strategy that targets the PI3K–mTOR pathway and GLI1 may lead to effective outcomes for PI3K pathway-dependent cancers, in contrast to recent results of human trials with single-agent PI3K antagonists.

Original languageEnglish (US)
Pages (from-to)4448-4459
Number of pages12
JournalCancer research
Volume77
Issue number16
DOIs
StatePublished - Aug 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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