CONTEXT

The Hedgehog (Hh) pathway plays a crucial role in stem cell self-renewal and tissue regeneration. Mutations that increase the overall activity of the pathway have been shown to be involved in the development of tumours in the lung, oesophagus, stomach, pancreas, biliary tract, breast, prostate, and brain. Many of these tumours contain cancer stem cells which present an aberrant Hh pathway activation and retain self-renewal properties representing a never-ending reservoir for the maintenance of the tumour mass. These cells are resistant to classical chemiotherapies because they express multidrug resistance proteins that efflux chemiotherapeutic agents from the cells. We demonstrated that the receptor of the Hh pathway Patched also contributes to the efflux of chemiotherapeutic agents such as doxorubicine.

TECHNICAL DESCRIPTION

Using an Hh-responding cell lines, yeast cells over-expressing human Patched and oocytes expiring human Patched, we demonstrated for the first time that the Hh receptor Patched is involved in doxorubicine efflux from the cells.

BENEFITS

The contribution of the receptor Patched in doxorubicine efflux from the cells is an important advance for the development of new anti-cancer therapies.  The receptor is present at the surface of cancer stem cells in which the Hh pathway is aberrantly activated. Therefore, the use of molecules able to inhibit the drug efflux activity of Patched should increase the efficacy of anti-cancer chemiotherapies. These new treatments should limit the development of metastasis link to aberrant Hh pathway activation.

INDUSTRIAL APPLICATIONS

Elaboration of molecules able to inhibit the drug efflux activity of Patched for the development of new anti-cancer therapies effective against cancer stem cells and metastasis.

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