Targeting epigenetic mechanisms to overcome venetoclax resistance

The BH-3 mimetic venetoclax overcomes apoptosis and therapy resistance caused by high expression of BCL2 or loss of BH3-only protein function. Although a promising therapy for hematologic malignancies, increased expression of anti-apoptotic MCL-1 or BCL-XL, as well as other resistance mechanisms prevent a durable response to venetoclax. Recent studies demonstrate that agents targeting epigenetic mechanisms such as DNA methyltransferase inhibitors, histone deacetylase (HDAC) inhibitors, histone methyltransferase EZH2 inhibitors, or bromodomain reader protein inhibitors may disable oncogenic gene expression signatures responsible for venetoclax resistance. Combination therapies including venetoclax and epigenetic therapies are effective in preclinical models and the subject of many current clinical trials. Here we review epigenetic strategies to overcome venetoclax resistance mechanisms in hematologic malignancies.

Automated summary

Venetoclax, a BH-3 mimetic, can overcome certain forms of therapy resistance in hematologic malignancies, but other resistance mechanisms still exist. Recent studies show that targeting epigenetic mechanisms can disable oncogenic gene expression responsible for venetoclax resistance, and combination therapies with venetoclax and epigenetic therapies are effective in preclinical models.