1. Academic Validation
  2. Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c)

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

  • Blood Cancer J. 2022 Jan 11;12(1):5. doi: 10.1038/s41408-021-00603-3.
Warren Fiskus 1 Steffen Boettcher 2 Naval Daver 1 Christopher P Mill 1 Koji Sasaki 1 Christine E Birdwell 1 John A Davis 1 Koichi Takahashi 1 Tapan M Kadia 1 Courtney D DiNardo 1 Qi Jin 1 Yuan Qi 1 Xiaoping Su 1 Gerard M McGeehan 3 Joseph D Khoury 1 Benjamin L Ebert 4 Kapil N Bhalla 5
Affiliations

Affiliations

  • 1 The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.
  • 2 University of Zurich and University Hospital Zurich, CH-8091, Zurich, Switzerland.
  • 3 Syndax Pharmaceuticals, Inc., Waltham, MA, 02451, USA.
  • 4 Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
  • 5 The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA. kbhalla@mdanderson.org.
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.

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