Identification of therapeutic targets sensitizing acute myeloid leukemia to BCL2 inhibitors
Shan Lin
PhDDana-Farber Cancer Institute
Project Term: July 1, 2019 - June 30, 2022
Venetoclax is a medication that can induce cell death of acute myeloid leukemia (AML), but its effectiveness needs to be further improved to benefit more patients. We are conducting a functional genetic screen to identify cooperating targets that enhance the efficacy of venetoclax and investigate the underlying molecular mechanism. Our study will provide valuable insights for understanding cell death regulation in AML and facilitating the clinical application of venetoclax for AML treatment.
This project aims to improve the effectiveness of ventoclax in a greater number of acute myeloid leukemia (AML) patients by targeting MARCH5 and other cell death sensitizers. AML is characterized by uncontrolled growth of abnormal white blood cells. Though current treatments are effective for some patients, the overall cure rate for AML remains unsatisfactory. Apoptosis is a type of normal cell death used to clear damaged or other unwanted cells. Apoptosis is tightly regulated through the balancing of pro-apoptotic and anti-apoptotic proteins mediated by the mitochondria. The evasion of apoptosis is a hallmark of all cancers and is essential for sustaining cancer growth. Thus, inhibition of these anti-apoptotic proteins provides a therapeutic strategy for treating AML. Venetoclax is an inhibitor of the anti-apoptotic protein BCL2 and shows promise in clinical studies. However, some AML patients develop resistance to venetoclax, sometimes through the compensatory increase of another anti-apoptotic protein, MCL1. This indicates that venetoclax will likely be most effective in combination with other drugs. The goal of my research is to identify cooperating targets that enhance the efficacy of venetoclax and thus to provide a rationale for designing combinational therapy that may benefit AML patients in the future. We identified the mitochondrial protein MARCH5 as a critical regulator of AML cell growth, and we showed that suppression of MARCH5 facilitates apoptosis in AML cells. Our preliminary data also suggests that suppression of MARCH5 enhances the effect of venetoclax on AML cells. This supports the rationale to study MARCH5 as a mediator of the anti-tumor effects of venetoclax in AML cells. We will define the mechanistic role of MARCH5 in AML by determining the critical targets regulated by MARCH5 and develop an understanding of how they might disrupt the evasion of apoptosis and promote venetoclax’s suppression of BCL2. We will determine if there is a connection between MARCH5 and MCL1, which may explain how MARCH5 counteracts BCL2 suppression. The translational value of targeting MARCH5 as a combined therapy with venetoclax will be evaluated using preclinical models that mimic the human disease. In addition, to expand our arsenal for enhancing the efficacy of venetoclax beyond MARCH5, we will perform a CRISPR-based, genome-scale screen in AML cell lines to systematically identify novel venetoclax sensitizers. Our study will provide valuable insights for understanding apoptosis regulation in AML and facilitating the clinical application of venetoclax for AML treatment.