Giving ALL a SMAC down (and HDAC down) towards cell death Free

In this issue of Blood, Saorin et al at the University Children’s Hospital Zurich and Baylor College of Medicine describe a critical new mechanism of necroptosis in acute lymphoblastic leukemia (ALL) driven by transcriptional regulation of receptor-interacting protein kinase 1 (RIPK1).¹ Although most children and adolescents with ALL can be cured with modern multiagent chemoimmunotherapy regimens,^2,3 drug resistance and/or relapse remains the leading cause of pediatric cancer mortality and highlights a persistent need for new treatment strategies. Appreciable interest exists in shifting the balance within leukemia cells from antiapoptosis survival mechanisms to proapoptosis death pathways via B-cell leukemia/lymphoma protein 2 inhibitors (eg, venetoclax) and other mechanisms of cell death, but the therapeutic potential of such approaches for children with ALL is not yet fully known.⁴ 

Using a large cadre of primary B-cell ALL (B-ALL) and T-cell ALL (T-ALL) specimens and patient-derived xenograft (PDX) models, the authors extend their prior observations of RIPK1-mediated leukemia cell death via small-molecule second mitochondria-derived activators of caspase (SMAC) mimetics⁵ in the present studies using comprehensive transcriptomic analysis, functional in vivo CRISPR screening, and ex vivo drug response profiling (DRP). They hypothesize that cotargeting of additional critical vulnerabilities within ALL cells can augment the incomplete therapeutic activity of SMAC mimetics observed to date in the clinic in patients with refractory leukemias or myeloproliferative neoplasms. The authors demonstrate transcriptional upregulation of tumor necrosis factor-α and NF-κB signaling pathways associated with RIPK1-driven necroptosis in short-term SMAC mimetic-treated B-ALL PDX cells and a critical role of histone deacetylases (HDACs), consistent with recent independent observations in preclinical T-ALL models⁶ and with earlier studies in B-ALL models.⁷ Saorin and colleagues also use their established high-throughput >100-compound DRP pipeline and matrix synergy screening to identify several agents that clearly augment the antileukemia activity of the SMAC mimetic birinapant, including HDAC inhibitors that have been recently evaluated in combination with chemotherapy in children with relapsed/refractory acute myeloid leukemia.⁸ Finally, the investigators validate their ex vivo data via in vivo studies in which they observed potent inhibition of leukemia proliferation with birinapant in combination with HDAC inhibitors mocetinostat, entinostat, or panobinostat with preferential activity in specific higher-risk genetic subtypes of B-ALL PDX models.

Taken together, these data convincingly demonstrate a key interaction of RIPK with previously unknown critical intracellular dependencies within pediatric B-ALL and T-ALL cells that can be successfully targeted with novel combinations of small-molecule inhibitors to induce necroptosis. Such strategies may provide an alternative approach to current apoptosis-targeting venetoclax-based regimens that remain partially effective, incompletely understood, and/or of limited access for pediatric patients with ALL to date. Importantly, this study also further credentials the clinical potential of this team’s high-throughput DRP assays to reveal new therapeutic vulnerabilities within childhood ALL cells,⁹ a strategy under current translational implementation via multi-institutional noninterventional observation studies using bone marrow specimens from pediatric (NCT06550102) or adult (NCT0348864¹⁰) patients with acute leukemias. However, the positive predictive value of this ex vivo DRP and in vivo PDX drug testing pipeline to match the right patient with the right medicine potentially beyond genetic mutation-driven inhibitor sensitivities has not yet been fully proven and requires prospective evaluation. Collaborative efforts are ongoing to implement DRP more broadly in umbrella trials in development of targeted therapies for pediatric patients with relapsed B-ALL and T-ALL (EudraCT number 2021-003398-79) and, if successfully predictive, will likely represent a true paradigm shift in precision medicine approaches for high-risk childhood leukemias.

Conflict-of-interest disclosure: The author declares no competing financial interests.