Resistance to the BCL-XL degrader DT2216 in T-cell acute lymphoblastic leukemia is rare and correlates with decreased BCL-XL proteolysis

• Published in: Cancer chemotherapy and pharmacology Vol. 91; no. 1; pp. 89 - 95
• Main Authors: Jaiswal, Arunima, Jaiswal, Aruna, Williamson, Elizabeth A., Gelfond, Jonathon, Zheng, Guangrong, Zhou, Daohong, Hromas, Robert
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-01-2023; Springer Nature B.V
• Subjects: Acute lymphoblastic leukemia; Animals; Apoptosis; Bcl-2 protein; Bcl-x protein; bcl-X Protein - metabolism; BIM protein; Cancer Research; Cell Line, Tumor; Cell survival; Clinical trials; Correlation; Cytotoxicity; Degradation; Humans; Leukemia; Lymphocytes T; Mcl-1 protein; Medicine; Medicine & Public Health; Mice; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Oncology; Pharmacology/Toxicology; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Proteins; Proteolysis; Proto-Oncogene Proteins c-bcl-2; Short Communication; Survival; T-Lymphocytes - metabolism; Tumor cell lines; Tumors; BCL-XL; PROTAC; T-cell acute lymphoblastic leukemia; Apoptosis
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-022-04490-8

Purpose
The BCL-2 family of anti-apoptotic proteins, BCL-2, BCL-XL and MCL-1, can mediate survival of some types of cancer. DT2216 is a PROteolysis-TArgeting Chimera (PROTAC) that degrades BCL-XL specifically and is in phase 1 trials. We sought to define the frequency and mechanism of resistance to DT2216 in T-cell acute lymphoblastic leukemia (T-ALL) cell lines.
Methods
We measured cell survival and protein levels of BCL-XL, BCL-2, MCL-1 and the pro-apoptotic BIM in 13 distinct T-ALL cell lines after exposure to varying concentrations of DT2216.
Results
We identified concentrations of DT2216 which were cytotoxic to each T-ALL cell line.
These concentrations have no correlation with the initial protein levels of BCL-XL, BCL-2, MCL-1 or BIM in each cell line. However, there was a correlation between survival to DT2216 and the efficiency of degradation of BCL-XL by DT2216. Only one cell line, SUP-T1, had significant resistance to DT2216, defined as an IC50 above what is achievable in murine tumors in vivo.
Conclusion
Resistance to DT2216 is rare in a wide variety of T-ALL cells but when it occurs is correlated with decreased BCL-XL degradation. Resistance to DT2216 in T-ALL is not predicted by initial BCL-XL or BIM protein levels, or BCL-2 or MCL-1 levels before or after treatment. These data imply that a phase 2 clinical trial of DT2216 in T-ALL should be widely available and not limited to a subset of patients.