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

ABSTRACT:

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,

SUBMITTER: Jaiswal A 

PROVIDER: S-EPMC10405225 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature