Epigenetic synthetic lethality in ovarian clear cell carcinoma: EZH2 and ARID1A mutations

Author's View - open access

 In addition to ARID1A mutation, the phosphoinositide 3-kinase (PI3K)/protein kinase B (best known as AKT), pathway is often activated in OCCC as a result of gain-of-function mutations in PIK3CA, the gene encoding the catalytic subunit of PI3K. Indeed, conditional Arid1a knockout together with activation of phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit α isoform (Pik3ca) leads to the development of OCCC in genetic mouse models.¹⁰ Interestingly, the validated ARID1A/EZH2 target gene PIK3IP1 is a negative regulator of PI3K. These findings suggest that ARID1A mutation cooperates with PI3K/AKT signaling to drive OCCC. Thus, a combination of the EZH2 inhibitor together with inhibition of the PI3K/AKT pathway may carry an even greater clinical benefit.