Division of Hematology and Medical Oncology, Department of Medicine and the Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
Division of Biostatistics, Department of Population Health Science, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
Cancer Chemother Pharmacol. 2023 Jan;91(1):89-95. doi: 10.1007/s00280-022-04490-8. Epub 2022 Nov 8.
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.
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.
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.
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.
BCL-2 家族的抗凋亡蛋白，BCL-2、BCL-XL 和 MCL-1，可以介导某些类型癌症的存活。DT2216 是一种 PROteolysis-TArgeting Chimera（PROTAC），可以特异性降解 BCL-XL，目前正在进行 I 期临床试验。我们试图确定 T 细胞急性淋巴细胞白血病（T-ALL）细胞系中对 DT2216 产生耐药的频率和机制。
我们在 13 种不同的 T-ALL 细胞系中，在不同浓度的 DT2216 作用后，测量细胞存活率和 BCL-XL、BCL-2、MCL-1 以及促凋亡 BIM 的蛋白水平。
我们确定了对每种 T-ALL 细胞系具有细胞毒性的 DT2216 浓度。这些浓度与每种细胞系中 BCL-XL、BCL-2、MCL-1 或 BIM 的初始蛋白水平无关。然而，DT2216 存活率与 DT2216 降解 BCL-XL 的效率之间存在相关性。只有一种细胞系，SUP-T1，对 DT2216 具有显著的耐药性，定义为 IC50 高于体内在鼠肿瘤中可达到的水平。
在广泛的 T-ALL 细胞中，对 DT2216 的耐药性罕见，但当发生时，与 BCL-XL 降解减少相关。T-ALL 对 DT2216 的耐药性不能通过初始 BCL-XL 或 BIM 蛋白水平，或治疗前后的 BCL-2 或 MCL-1 水平来预测。这些数据表明，DT2216 在 T-ALL 中的 II 期临床试验应该广泛可用，而不仅仅局限于一部分患者。
