Hedgehog-GLI Signaling Inhibition Suppresses Tumor Growth in Squamous Lung Cancer
Lung squamous cell carcinoma (LSCC) comprises ~30% of non-small cell lung cancers, and currently lacks effective targeted therapies. Previous immunohistochemical and microarray 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 pathway suppression.
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 <italic>in vivo<italic> efficacy of GLI inhibitor GANT61.
In both patient cohorts, we found that activation of HH-GLI signaling was significantly associated with the classical subtype of LSCC. <italic>GLI2<italic> expression level was significantly higher than <italic>GLI1<italic>, and displayed strong positive correlations with the prominent markers for the classical subtype (<italic>SOX2<italic>, <italic>TP63<italic> and <italic>PIK3CA<italic>) on chromosome 3q. In cell lines, genetic knockdown of SMO produced minor effects on cell survival, while 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 <italic>in vivo<italic> anti-tumor activity in xenograft models of GLI-positive cell lines.
Taken together, we report SMO-independent regulation of GLI in LSCC, and demonstrate an important role for GLI2 in LSCC. Different from standard-of-care chemotherapy or small molecule inhibition of kinase signaling cascades, we present a novel and potent strategy to treat a subset of LSCC patients by targeting the GLI transcriptional network.
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