Selective inhibition of MCL1 overcomes venetoclax resistance in a murine model of myelodysplastic syndromes

Treatment for myelodysplastic syndromes (MDS) remains insufficient due to clonal heterogeneity and lack of effective clinical therapies. Dysregulation of apoptosis is observed across MDS subtypes regardless of mutations and represents an attractive therapeutic opportunity. Venetoclax (VEN), a select...

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Published inHaematologica (Roma) Vol. 108; no. 2; pp. 522 - 531
Main Authors Fischer, Melissa A., Song, Yuanbin, Arrate, Maria P., Gbyli, Rana, Villaume, Matthew T., Smith, Brianna N., Childress, Merrida A., Stricker, Thomas P., Halene, Stephanie, Savona, Michael R.
Format Journal Article
LanguageEnglish
Published Italy Fondazione Ferrata Storti 01.02.2023
Ferrata Storti Foundation
Subjects
Animals
Apoptosis
Bridged Bicyclo Compounds, Heterocyclic - pharmacology
Bridged Bicyclo Compounds, Heterocyclic - therapeutic use
Cell Line, Tumor
Disease Models, Animal
Leukemia, Myeloid, Acute - genetics
Mice
Myelodysplastic Syndromes
Myelodysplastic Syndromes - drug therapy
Myelodysplastic Syndromes - genetics
Myelodysplastic Syndromes - metabolism
Myeloid Cell Leukemia Sequence 1 Protein - metabolism
Proto-Oncogene Proteins c-bcl-2
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Summary:Treatment for myelodysplastic syndromes (MDS) remains insufficient due to clonal heterogeneity and lack of effective clinical therapies. Dysregulation of apoptosis is observed across MDS subtypes regardless of mutations and represents an attractive therapeutic opportunity. Venetoclax (VEN), a selective inhibitor of anti-apoptotic protein B-cell lymphoma- 2 (BCL2), has yielded impressive responses in older patients with acute myeloid leukemia (AML) and high risk MDS. BCL2 family anti-apoptotic proteins BCL-XL and induced myeloid cell leukemia 1 (MCL1) are implicated in leukemia survival, and upregulation of MCL1 is seen in VEN-resistant AML and MDS. We determined in vitro sensitivity of MDS patient samples to selective inhibitors of BCL2, BCL-XL and MCL1. While VEN response positively correlated with MDS with excess blasts, all MDS subtypes responded to MCL1 inhibition. Treatment with combined VEN + MCL1 inhibtion was synergistic in all MDS subtypes without significant injury to normal hematopoiesis and reduced MDS engraftment in MISTRG6 mice, supporting the pursuit of clinical trials with combined BCL2 + MCL1 inhibition in MDS.
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MRS has served on consultancy/advisory board/data safety monitoring committees for Abbvie, BMS, CTI, Forma, Geron, Karyopharm, Novartis, Ryvu, Sierra Oncology, Takeda, Taiho TG Therapeutics; has equity in Karyopharm; and his institution has received research funding from ALX Oncology, Incyte, Takeda, and TG Therapeutics. SH serves on the advisory board of FORMA Therapeutics.
Disclosures
Contributions
MAF, YS, and RG designed and performed experiments. MPA, and MTV performed experiments. MAF, YS, RG, MPA, MTV, MAC, BNS, TPS, SH, and MRS analyzed data. MAF and MRS performed statistical analysis and wrote the manuscript. SH and MRS designed and supervised the study. All authors reviewed and edited drafts of the manuscript and approved the final version of the manuscript.
Data-sharing statement
Not applicable as data generated in this study have been included in the published article.
ISSN:0390-6078
1592-8721
1592-8721
DOI:10.3324/haematol.2022.280631