CEMIP, a new player in the acquired resistance to targeted therapies

Alain Chariot's team (Laboratory of Medical Chemistry) shows that the CEMIP protein plays a role in resistance to targeted therapies for colorectal cancers. By associating one targeted therapy with a pharmacological treatment that inhibits this protein, we could treat relapses in patients with this type of tumor.

C

olorectal cancer is the second leading cause of death from cancer in Western countries and arises from a variety of genetic alterations.

The treatment of solid tumors such as intestinal cancers now involves therapies that specifically target oncogenic proteins showing some activating mutations or aberrantly expressed. These targeted therapies holded some promise but turned out to be disappointing in many cases due to some acquired resistance in many patients. It is now well accepted that only combinatory therapies will trigger some prolonged tumor regression with a significant gain of life span.

We generated new experimental models of intestinal cancer cells showing some acquired resistance to Selumetinib, a MEK1 inhibitor. These experimental models (2D cancer cell lines and ex-vivo Selumetinib-resistant intestinal organoids) showed elevated levels of CEMIP. This scaffold protein is critically involved in ERK1/2 reactivation, a key molecular event required for the acquired resistance to Selumetinib. Mechanistically, CEMIP is found in signaling endosomes, binds MEK1 and stabilizes the oncogenic protein MYC through ERK1/2 activation. These resistant cells undergo some metabolic reprogramming thanks to stabilized MYC. This reprogramming includes the production of specific amino acids linked to the acquired resistance. The depletion of CEMIP resensitizes resistant cells to Selumetinib-dependent cell death, at least through decreased ERK1/2 activation and protein levels of MYC. Therefore, this study defines CEMIP as a new player involved in the acquired resistance to a targeted therapy and may define a new combinatory therapy to better treat intestinal tumors.

Illustration of a Selumetinib-resistant ex-vivo organoid from Apc-mutated intestinal crypts. All cells are in blue (DAPI staining). Proliferative cells are in light blue (Ki67 staining) while dying/apoptotic cells are stained in pink (activated Caspase 3 staining).

Scientific reference

Hong Quan Duong, Ivan Nemazanyy, Florian Rambow, Seng Chuan Tang, Sylvain Delaunay, Lars Tharun, Alexandra Florin, Reinhard Büttner, Daniel Vandaele, Pierre Close, Jean-Christophe Marine, Kateryna Shostak* and Alain Chariot^*. *Equal contributions. The endosomal protein CEMIP links Wnt signaling to MEK1-ERK1/2 activation in Selumetinib-resistant intestinal organoids. Cancer Research (2018), in press.

Financial support:

FNRS, Université de Liège, Fondation Belge contre le cancer, WELBIO, Fonds Léon Fredericq, Centre Anticancéreux du CHU de Liège