TL-895, a Highly Selective, Covalent Inhibitor of Bruton's Tyrosine Kinase (BTK), Sensitizes Myeloproliferative Neoplasm (MPN)-Blast Phase Stem Cells to Navtemadlin By Targeting Intrinsic Dysregulated MDM2/p53 and NF-Κb Pathways and Disrupting the Protective Tumor Microenvironment (TME)

• Published in: Blood 2023-11, Vol.142 (Supplement 1), p.4523-4523
• Main Authors: Wang, Xiaoli, Davis, Andrew, Su, Xiaoping, Muftuoglu, Muharrem, Krejsa, Cecile, Mascarenhas, John, Andreeff, Michael, Hoffman, Ronald
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2023-187426

We recently reported that navtemadlin (nvtm), a potent, orally available, selective inhibitor of MDM2 (MDM2i), can deplete/eliminate TP53WT MPN-blast phase (BP) stem cells (SC) in an MPN-BP patient (pt)-derived xenograft (PDX) model (Wang EHA 2023). Single agent nvtm has demonstrated significant clinical activity in pts with advanced myelofibrosis (MF) (Vachhani EHA 2023, Verstovsek Future Oncology 2022). We hypothesized that effects of nvtm on MPN-BP, which is characterized by multiple SC subclones, could be enhanced by combination with agents that target additional MPN-BP SC vulnerabilities, such as hyperactivation of p65 subunit of NF-κB (Fisher Leukemia 2017; our unpublished data) and dependence on TME support. BTK and bone marrow (BM) kinase X-linked (BMX) are key Tec family members expressed in cells of myeloid origin. Here, we show BTK is constitutively activated in MPN-BP SC subpopulations relative to normal donor (ND) hematopoietic SCs (HSC) and progenitors [phospho (p)-BTK Y233 mean fluorescence intensity fold change (FC)]: CD34 +CD38 - cells: 1.34±0.18, HSC/multipotent progenitor (MPP): 1.50±0.23, multi-lymphoid progenitor (MLP): 1.59±0.59, megakaryocyte-erythroid progenitor (MEP): 1.56±0.49; p