Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c)

Abstract

Treatment with Menin inhibitor (MI) disrupts the interaction between Menin and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation and loss of survival of AML harboring MLL1 re-arrangement (r) and FP, or expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, the majority of patients with AML with MLL1-r or mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout or degradation of Menin or treatment with the MI SNDX-50469 reduces MLL1/MLL1-FP targets, associated with MI-induced differentiation and loss of viability. MI treatment also attenuates BCL2 and CDK6 levels. Co-treatment with SNDX-50469 and BCL2 inhibitor (venetoclax), or CDK6 inhibitor (abemaciclib) induces synergistic lethality in cell lines and patient-derived AML cells harboring MLL1-r or mtNPM1. Combined therapy with SNDX-5613 and venetoclax exerts superior in vivo efficacy in a cell line or PD AML cell xenografts harboring MLL1-r or mt-NPM1. Synergy with the MI-based combinations is preserved against MLL1-r AML cells expressing FLT3 mutation, also CRISPR-edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1-r or mtNPM1.

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

“…S2C). Ziftomenib also increased MCL1 levels, unlikely due to MEK inhibition, as previously reported [10]. Genetic lesion(s) in TP53 were documented in approximately 9% of patients with MLL1-r AML [10].…”

“…1A, Supplementary Figs. S1C and S1D) [10]. Treatment with ziftomenib for 4 days dose-dependently induced loss of viability in OCI-AML3 and MV4-11 cells, but less so in MOLM13 and was ineffective in THP1 or NOMO-1 cells (Fig.…”

“…Additionally, in AML with mtNPM1 (NPM1c), MLL1 is the main oncogenic regulator of HOXA9, MEIS1 and FLT3, promoting self-renewal of myeloid progenitor cells [2,6,7]. 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][9][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 [2,11].…”

Molecular Classification and Overcoming Therapy Resistance for Acute Myeloid Leukemia with Adverse Genetic Factors

“…Fiskus and colleagues also demonstrated that the menin-KMT2A inhibitor SNDX-50469 induced differentiation and reduced the viability of the leukemic cell lines with KMT2A r or NPM mt, which was accompanied by the attenuation of BCL-2 and cyclin-dependent kinase 6 (CDK6) levels. Interestingly, the concurrent administration of SNDX-50469 with a BCL-2 inhibitor or a CDK6 inhibitor led to synergistic lethality [ 149 ]. Combination therapy with memin-KMT2A inhibitors and FLT3 inhibitors represents a promising strategy for AML with KMT2A -r or NPM1 mt and concurrent FLT3 mutation ( KMT2A r/ NPM1 mt- FLT3 mt).…”

Overcoming Resistance: FLT3 Inhibitors Past, Present, Future and the Challenge of Cure

“…Menin inhibitors showed a potential activity in NPM1mut AML, related to MLL1 and MLL1-fusion protein inhibition. Menin inhibitors also inactivate MEIS1 transcription factor with the particularly interesting effect of downregulating its transcriptional target gene FLT3, suggesting a possible synergy with FLT3i, especially in NPM1mut-FLT3mut AML, and also in MLL-FLT3mut AML [ 115 ]. Researchers have recently demonstrated that the inhibitory effect of menin inhibitors on BCL2 protein is synergistic with that of Venetoclax in NPM1mut-FLT3mut AML [ 116 ].…”