Alexey Danilov, MD, Ph.D., associate director of the Toni Stephenson Lymphoma Center at City of Hope speaks about the AACR 2021 Abstract – 938 – Pharmacologic targeting Mcl-1 with AZD5991 induces apoptosis, suppresses mitochondrial respiration, and overcomes ibrutinib resistance in non-Hodgkin lymphoma cells.
Link to Abstract:
https://www.abstractsonline.com/pp8/#!/9325/presentation/2449
Synopsis:
Pro-apoptotic “initiators” (Noxa, Bim, Puma), anti-apoptotic “guardians” (Bcl-2, Mcl-1, Bcl-xL), and pro-apoptotic effectors (Bax/Bak) are all members of the Bcl-2 family of proteins. Venetoclax, a Bcl-2 receptor, has been approved by the Food and Drug Administration for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia. Venetoclax, on the other hand, is only moderately successful in non-Hodgkin lymphoma (NHL). Mcl-1 is a short-lived pro-survival protein that is overexpressed often in NHL, resulting in improved cell survival and drug resistance. Mcl-1 transgenic mice develop lymphoma that is aggressive. As a result, selective targeting of Mcl-1 in NHL is a promising pharmacologic approach. AZD5991 is a highly selective small-molecule inhibitor of Mcl-1 that has recently reached clinical trials. In this study, we looked at its preclinical behavior in NHL. Mcl-1 expression was discovered in ten DLBCL cell lines, as well as parental/ibrutinib-resistant JeKo-1 and Mino mantle cell lymphoma (MCL) cell lines. In DLBCL cells, as well as parental/ibrutinib-resistant MCL cells, AZD5991 inhibited proliferation and induced apoptosis in a dose-dependent manner. In both DLBCL and parental/ibrutinib-resistant MCL cells, Mcl-1 inhibition caused mitochondrial dysfunction, including mitochondrial membrane depolarization, decreased mitochondrial mass, increased mitophagy, and increased reactive oxygen species levels. According to the Seahorse assay, Mcl-1 inhibition reduced basal and maximal respiratory ability in susceptible but not immune cells, meaning that mitochondrial compromise is a function of susceptibility to Mcl-1 inhibition. AZD5991 showed synergy with other BH3-mimetics, according to an inhibitors screening assay. Resistance to AZD5991 was overcome by co-treating DLBCL cells with the Bcl-2/xL antagonists AZD4320, venetoclax, and navitoclax. Finally, Primary MCL cells were co-cultured with power, CD40L-, or BAFF-expressing stroma, which induced resistance to spontaneous and drug-induced apoptosis and partly mimicked the lymph node microenvironment. In both the control and BAFF-expressing conditions, Mcl-1 inhibition resulted in apoptosis of primary MCL cells, which was followed by a decline in mitochondrial respiration. Meanwhile, AZD5991 security was given by CD40L stroma, which was partially resolved by co-treatment with venetoclax. In a subset of DLBCL, parental/ibrutinib-resistant MCL cells, and predominant neoplastic B cells, Mcl-1 inhibition using the selective BH3-mimetic AZD5991 inhibits cell proliferation and induces apoptosis. Mcl-1 inhibition causes mitochondrial dysfunction and cellular respiration inhibition. In NHL, resistance to Mcl-1 inhibition could be eliminated by attacking alternative anti-apoptotic proteins (Bcl-2/xL) at the same time.