Blocking SHH/Patched interaction triggers tumor growth inhibition through Patched-induced apoptosis

The Sonic Hedgehog (SHH) pathway plays a key role in cancer. Alterations of SHH canonical signaling, causally linked to tumor progression, have become rational targets for cancer therapy. However, Smoothened (Smo) inhibitors have failed to show clinical benefit in patients with cancers displaying SHH autocrine/paracrine expression. We reported earlier that the SHH receptor Patched (Ptc) is a dependence receptor that triggers apoptosis in the absence of SHH through a pathway that differs from the canonical one, thus generating a state of dependence on SHH for survival. Here, we propose a dual function for SHH: its binding to Ptc not only activates the SHH canonical pathway but also blocks Ptc-induced apoptosis. 80%, 64% and 8% of human colon, pancreatic and lung cancer cells, respectively, overexpressed SHH at transcriptional and protein levels. In addition, SHH-overexpressing cells expressed all the effectors of the Ptc-induced apoptotic pathway. While the canonical pathway remained unchanged, autocrine SHH interference in colon, pancreatic and lung cell lines triggered cell death through Ptc pro-apoptotic signaling. In vivo, SHH interference in colon cancer cell lines decreased primary tumor growth and metastasis. Therefore, the anti-tumor effect associated to SHH deprivation, usually thought to be a consequence of the inactivation of the canonical SHH pathway, is due to the engagement of Ptc pro-apoptotic activity. Together, these data strongly suggest that therapeutic strategies based on the disruption of SHH/Ptc interaction in SHH-overexpressing cancers should be explored.