Abstract
Inhibition of Hedgehog (HH)/GLI signalling in cancer is a promising therapeutic approach. Interactions between HH/GLI and other oncogenic pathways affect the strength and tumourigenicity of HH/GLI. Cooperation of HH/GLI with epidermal growth factor receptor (EGFR) signalling promotes transformation and cancer cell proliferation in vitro. However, the in vivo relevance of HH-EGFR signal integration and the critical downstream mediators are largely undefined. In this report we show that genetic and pharmacologic inhibition of EGFR signalling reduces tumour growth in mouse models of HH/GLI driven basal cell carcinoma (BCC). We describe HH-EGFR cooperation response genes including SOX2, SOX9, JUN, CXCR4 and FGF19 that are synergistically activated by HH-EGFR signal integration and required for in vivo growth of BCC cells and tumour-initiating pancreatic cancer cells. The data validate EGFR signalling as drug target in HH/GLI driven cancers and shed light on the molecular processes controlled by HH-EGFR signal cooperation, providing new therapeutic strategies based on combined targeting of HH-EGFR signalling and selected downstream target genes.
Highlights
Malignant transformation is a multistep process that involves cooperation of oncogenic signals to determine the malignant state of a cell (Hanahan & Weinberg, 2000)
Since activation of RAS-MEK/ERK is a common event in response to receptor tyrosine kinase (RTK) activation, we addressed whether the activation of HH/GLI-epidermal growth factor receptor (EGFR) response genes is mediated by combined GLI and EGFR signalling, or whether other RTK pathways can cooperate with GLI and induce a similar cooperation response gene profile
An intriguing finding of this study was that our systematic screen for downstream mediators of the synergistic transformation effect identified a set of HH-EGFR cooperation response genes (CRG) that is directly regulated by GLI, synergistically enhanced by EGFR signalling and enriched for critical determinants of the oncogenic phenotype of both basal cell carcinoma (BCC) and tumour-initiating pancreatic cancer cells (i.e. JUN, SOX9, SOX2, FGF19 and CXCR4)
Summary
Malignant transformation is a multistep process that involves cooperation (i.e. synergistic interaction) of oncogenic signals to determine the malignant state of a cell (Hanahan & Weinberg, 2000). SMOindependent stimulation of GLI activity via interactions with RAS-MEK/ERK, PI3K/AKT (Riobo et al, 2006a; Riobo et al, 2006b; Stecca et al, 2007) or growth factor pathways such as TGFb (Dennler et al, 2009; Nolan-Stevaux et al, 2009) and epidermal growth factor receptor (EGFR) signalling (Kasper et al, 2006a; Palma et al, 2005; Palma & Ruiz i Altaba, 2004; Schnidar et al, 2009) may bypass or attenuate the therapeutic efficacy of SMO antagonists in malignant diseases such as melanoma or pancreatic cancer
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