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

Cancer Chemother Pharmacol. 2023 Jan;91(1):89-95. doi: 10.1007/s00280-022-04490-8. Epub 2022 Nov 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.

Keywords: Apoptosis; BCL-XL; PROTAC; T-cell acute lymphoblastic leukemia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Line, Tumor
  • Humans
  • Mice
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy
  • Proteolysis
  • Proto-Oncogene Proteins c-bcl-2
  • T-Lymphocytes / metabolism
  • bcl-X Protein / metabolism


  • DT2216
  • bcl-X Protein
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins c-bcl-2