PP2A SUBUNITS IN DNA REPAIR, THE PP2A B55α SUBUNIT AS NOVEL PHD2 INTERACTING PROTEIN, AND IMPLICATIONS FOR CANCER

摘要

The present application relates to the field of cancer treatment. In a first aspect, it particularly relates to treatment of cancers by using the concept of synthetic lethality. It is shown that suppression or loss of function of particular subunits of the heterotrimeric serine/threonine phosphatases 2A (PP2A) sensitizes cells to inhibition of DNA base excision repair, such as e.g. PARP inhibition. These findings can be used to screen for patients sensitive to therapies based on DNA base excision repair inhibition, as well as used therapeutically by administering inhibitors of PP2A subunits, particular in combination with inhibitors of DNA base excision repair, such as PARP inhibitors. Interestingly, it is also shown that a particular PP2A subunit, B55α, is a novel interacting protein of the oxygen sensor PHD2. Both proteins are negative regulators of each other, and it is shown herein that B55α in tumor cells leads to apoptosis of these cells and thus to smaller tumors. Thus, inhibitors of the PP2A B55α subunit as such can also be used therapeutically in the treatment of cancer.