Biomarker-driven strategy for MCL1 inhibition in T-cell lymphomas
Open Access
- 7 February 2019
- journal article
- research article
- Published by American Society of Hematology in Blood
- Vol. 133 (6), 566-575
- https://doi.org/10.1182/blood-2018-07-865527
Abstract
There is a pressing need for more effective therapies to treat patients with T-cell lymphomas (TCLs), including first-line approaches that increase the response rate to cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) chemotherapy. We characterized the mitochondrial apoptosis pathway in cell lines and patient-derived xenograft (PDX) models of TCL and assessed the in vitro efficacy of BH3 mimetics, including the BCL2 inhibitor venetoclax, the BCL2/BCL-xL inhibitor navitoclax, and the novel MCL1 inhibitor AZD5991. The abundance of antiapoptotic BCL2 family members based on immunoblotting or RNA transcript levels correlated poorly with the activity of BH3 mimetics. In contrast, the functional approach BH3 profiling reliably predicted sensitivity to BH3 mimetics in vitro and in vivo. We used BH3 profiling to select TCL PDX that were dependent on MCL1. Mice xenografted with these PDX and treated with AZD5991 had markedly improved survival. The combination of AZD5991 and CHOP achieved synergy based on survival improvement beyond a mathematical “sum of benefits” model. Thus, MCL1 inhibition is a promising strategy as both a single agent and in combination with chemotherapy for patients with TCL and functional dependence on MCL1.Keywords
This publication has 31 references indexed in Scilit:
- Designed BH3 Peptides with High Affinity and Specificity for Targeting Mcl-1 in CellsACS Chemical Biology, 2014
- How I treat the peripheral T-cell lymphomasPublished by American Society of Hematology ,2014
- Survival of Patients With Peripheral T-Cell Lymphoma After First Relapse or Progression: Spectrum of Disease and Rare Long-Term SurvivorsJournal of Clinical Oncology, 2013
- Results From a Pivotal, Open-Label, Phase II Study of Romidepsin in Relapsed or Refractory Peripheral T-Cell Lymphoma After Prior Systemic TherapyJournal of Clinical Oncology, 2012
- Pralatrexate in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma: Results From the Pivotal PROPEL StudyJournal of Clinical Oncology, 2011
- Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activityThe Lancet Oncology, 2010
- International Peripheral T-Cell and Natural Killer/T-Cell Lymphoma Study: Pathology Findings and Clinical OutcomesJournal of Clinical Oncology, 2008
- BCL‐2 family proteins in peripheral T‐cell lymphomas: correlation with tumour apoptosis and proliferationThe Journal of Pathology, 2003
- The Hallmarks of CancerCell, 2000
- THE TOXICITY OF POISONS APPLIED JOINTLY1Annals of Applied Biology, 1939