Cooperative Hedgehog-EGFR signaling

Abstract

It has been known for many years that cooperative interactions between oncogenes (e.g. RAS, MYC, BCL2) can fuel cancer growth (1-5), but the restricted druggability of many of those interacting cancer genes has hampered translation of combined targeting to medical cancer therapy. The identification and characterization of cooperative cancer signaling pathways amenable to medical therapy is therefore a crucial step towards the establishment of efficient targeted combination treatments urgently needed to improve cancer therapy. Here we review recent findings of our group and colleagues on the molecular mechanisms of cooperative Hedgehog/GLI and Epidermal Growth Factor Receptor (EGFR) signaling, two clinically relevant oncogenic pathways involved in the development of many human malignancies. We also discuss the possible implications of these findings for the design of a therapeutic regimen relying on combined targeting of key effectors of both pathways.

Fig1

Model of cooperative HH/GLI-EGFR signal integration in malignant transformation. A) Activation of a canonical GLI target gene expression profile in the absence of parallel EGFR signaling. B) Simultaneous stimulation of HH/GLI and EGFR signaling results in the synergistic activation of HH/GLI-EGFR cooperation response genes (CRG) thereby promoting malignant transformation. HH/GLI-EGFR CRG are transcriptionally controlled by cooperative interactions of the GLI activator forms (GLI-A) and JUN/AP1 transcription factor complexes at the promoters of HH/GLI-EGFR CRG. Activation of JUN/AP1 transcriptional regulators (indicated by phosphorylation symbols) involves EGFR-dependent activation of the RAS/RAF/MEK/ERK cascade.