HSP90 Inhibitor PU-H71 in Combination with BH3-Mimetics in the Treatment of Acute Myeloid Leukemia

Abstract

Targeting the molecular chaperone HSP90 and the anti-apoptotic proteins MCL1 and BCL2 may be a promising novel approach in the treatment of acute myeloid leukemia (AML). The HSP90 inhibitor PU-H71, MCL1 inhibitor S63845, and BCL2 inhibitor venetoclax were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells. AML cells represented all major morphologic and molecular subtypes including FLT3-ITD and TP53 mutant AML cell lines and a variety of patient-derived AML cells. Results: PU-H71 and combination treatments with MCL1 inhibitor S63845 or BCL2 inhibitor venetoclax induced cell cycle arrest and apoptosis in susceptible AML cell lines and primary AML. The majority of the primary AML samples were responsive to PU-H71 in combination with BH3 mimetics. Elevated susceptibility to PU-H71 and S63845 was associated with FLT3 mutated AML with CD34 < 20%. Elevated susceptibility to PU-H71 and venetoclax was associated with primary AML with CD117 > 80% and CD11b < 45%. The combination of HSP90 inhibitor PU-H71 and MCL1 inhibitor S63845 may be a candidate treatment for FLT3-mutated AML with moderate CD34 positivity while the combination of HSP90 inhibitor PU-H71 and BCL2 inhibitor venetoclax may be more effective in the treatment of primitive AML with high CD117 and low CD11b positivity.

FLT3 and IRAK4 Inhibitor Emavusertib in Combination with BH3-Mimetics in the Treatment of Acute Myeloid Leukemia

“…Combining emavusertib with other anticancer therapies may be a more effective treatment strategy. In order to define effective treatment combinations, we focused on inhibitors expected to elicit synergistic cytotoxic effects in combination with CA4948 based on previous studies with BCL2, MCL1, and HSP90 inhibitors [7,8,35]. FLT3-ITD-positive MOLM-13 cells were susceptible to CA4948, S63845, venetoclax, or PU-H71, with enhanced effects on cell viability in the combination treatments.…”

“…MCL1 and BCL2 proteins are both frequently overexpressed in AML and critical for the survival of AML cells and leukemic stem cells [4]. While the BCL2 inhibitor venetoclax, in combination with azacitidine, decitabine, or low-dose cytarabine (LDAC), has been approved for the treatment of adults with newly diagnosed AML [5], the MCL1 inhibitor S63845 has been evaluated as a candidate treatment in AML in combination with the MEK inhibitor trametinib, the BMI1 inhibitor PTC596, or the HSP90 inhibitor PU-H71 in preclinical studies [6][7][8].…”

“…Combining HSP90 inhibitors with other anticancer therapies might be a more advisable strategy to reduce toxicity and increase efficacy [24]. The combination of the HSP90 inhibitor PU-H71 and the MCL1 inhibitor S63845 may be a candidate treatment for FLT3-mutated AML with moderate CD34 positivity, while the combination of HSP90 inhibitor PU-H71 and BCL2 inhibitor venetoclax may be more effective in the treatment of primitive AML with high CD117 and low CD11b positivity [8].…”