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GLI1 Blockade Potentiates the Antitumor Activity of PI3K Antagonists in Lung Squamous Cell Carcinoma
Sahba Kasiri1, Chunli Shao1, Baozhi Chen1
1Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research and Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
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. Cancer Res; 77(16); 4448-59. ©2017 AACR.
Insights
The Hedgehog pathway's GLI1 is a key driver in lung squamous cell carcinoma (SCC). Targeting GLI1 and the PI3K pathway offers a promising therapeutic strategy for SCC, improving upon single-agent approaches.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Lung squamous cell carcinoma (SCC) lacks targeted therapies, relying on traditional chemotherapy.
- The Hedgehog pathway, specifically the transcription factor GLI1, is implicated in cancer development.
Purpose of the Study:
- To investigate the role of GLI1 as a driver in lung SCC.
- To explore therapeutic strategies targeting GLI1 and related pathways in lung SCC.
Main Methods:
- Analysis of human lung cancer datasets to assess GLI1 expression and prognosis.
- Inhibition of GLI1 in lung SCC cell lines and *in vivo* models.
- Investigating the modulation of GLI1 by PI3K and MAPK pathways.
- Evaluating combinatorial therapy targeting GLI1 and PI3K in PIK3CA-amplified SCC.
Main Results:
- GLI1 mRNA was highly expressed in lung SCC, correlating with poor prognosis.
- GLI1 inhibition reduced SCC cell clonogenicity and proliferation *in vitro* and *in vivo*.
- GLI1 expression was regulated by PI3K and MAPK pathways, not directly by Hedgehog ligands.
- Combined GLI1 and PI3K antagonism inhibited *in vivo* growth of PIK3CA-amplified SCC.
Conclusions:
- GLI1 is a critical driver of lung SCC.
- Targeting GLI1, particularly in combination with PI3K pathway inhibitors, presents a viable therapeutic strategy for PI3K pathway-dependent lung SCC.
