Activity of menin inhibitor ziftomenib (KO-539) as monotherapy or in combinations against AML cells with MLL1 rearrangement or mutant NPM1

著者: Warren Fiskus, Naval Daver, Steffen Boettcher, Christopher P. Mill, Koji Sasaki, Christine Birdwell, John A. Davis, Kaberi Das, Koichi Takahashi, Tapan M. Kadia, Courtney D. DiNardo, Francis Burrows, Sanam Loghavi, Joseph D. Khoury, Benjamin L. Ebert, Kapil N. Bhalla - Leukemia 2022 被引用: 80

In MLL1-rearranged AML (MLL1-r), the MLL1 fusion protein (MLL-FP) causes dysregulated expression of HOXA9, MEIS1, PBX3, MEF2C and CDK6 HOXA9 and its co-factor MEIS1 are leukemogenic in myeloid stem progenitor cells Additionally, in AML with mtNPM1 (NPM1c), MLL1 is the main oncogenic regulator of HOXA9, MEIS1 and FLT3, promoting self-renewal of myeloid progenitor cells Orally bioavailable, investigational or clinical drug candidate Menin inhibitors (MIs) disrupt binding of Menin to its binding pocket in MLL1/2 and MLL1-FP, which reduces MLL1/2 and MLL1-FP binding to their targets, inhibits HOXA9/MEIS1 activity, represses PBX3, MEF2C, FLT3 and CDK6, as well as induces differentiation and loss of survival of AML with MLL1-r or with mutant (mt)-NPM1 [2, 8-10]. In early clinical trials, monotherapy with MI is well tolerated and has achieved objective remissions in patients with previously treated relapsed/ refractory AML harboring MLL1-r or NPM1c However, most patients either fail to respond or eventually relapse Therefore, there is a need to investigate the activity of additional MIs and MIbased combinations that may exhibit superior activity and prevent or abrogate MI-resistance in AML cells with MLL1-r or mtNPM1.