Dual Targeting of Apoptotic and Signaling Pathways in T-Lineage Acute Lymphoblastic Leukemia

被引:11
作者
Saygin, Caner [7 ,8 ]
Giordano, Giorgia
Shimamoto, Kathryn
Eisfelder, Bart
Thomas-Toth, Anika [1 ]
Venkataraman, Girish [2 ]
Ananthanarayanan, Vijayalakshmi [3 ]
Vincent, Tiffaney L. [4 ,5 ]
DuVall, Adam
Patel, Anand A.
Chen, Yi [6 ]
Tan, Fenlai [6 ]
Anthony, Stephen P. [6 ]
Chen, Yu [6 ]
Shen, Yue [6 ]
Odenike, Olatoyosi
Teachey, David T. [4 ,5 ]
Kee, Barbara L. [2 ]
LaBelle, James [1 ]
Stock, Wendy
机构
[1] Univ Chicago, Dept Med, Sect Hematol Oncol, Chicago, IL USA
[2] Univ Chicago, Dept Pediat, Chicago, IL USA
[3] Univ Chicago, Dept Pathol, Chicago, IL USA
[4] Loyola Univ Med Ctr, Dept Pathol, Chicago, IL USA
[5] Childrens Hosp Philadelphia, Philadelphia, PA USA
[6] Univ Penn, Perelman Sch Med, Sylvania, SK, Canada
[7] Newave Pharmaceut Inc, Pleasanton, CA USA
[8] Univ Chicago, Dept Med, Sect Hematol Oncol, Chicago, IL 60637 USA
关键词
BCL-2; VENETOCLAX; IBRUTINIB;
D O I
10.1158/1078-0432.CCR-23-0415
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: Relapsed T-acute lymphoblastic leukemia (T-ALL) has limited treatment options. We investigated mechanisms of resis-tance to BH3 mimetics in T-ALL to develop rational combination strategies. We also looked at the preclinical efficacy of NWP-0476, a novel BCL-2/BCL-xL inhibitor, as single agent and combination therapy in T-ALL.Experimental Design: We used BH3 profiling as a predictive tool for BH3 mimetic response in T-ALL. Using isogenic control, venetoclax-resistant (ven-R) and NWP-0476-resistant (NWP-R) cells, phosphokinase array was performed to identify differentially regulated signaling pathways.Results: Typical T-ALL cells had increased dependence on BCL-xL, whereas early T-precursor (ETP)-ALL cells had higher BCL-2 dependence for survival. BCL-2/BCL-xL dual inhibitors were effective against both subtypes of T-lineage ALL. A 71-protein human phosphokinase array showed increased LCK activity in ven-R cells, and increased ACK1 activity in ven-R and NWP-R cells. We hypothesized that pre-TCR and ACK1 signaling path-ways are drivers of resistance to BCL-2 and BCL-xL inhibition, respectively. First, we silenced LCK gene in T-ALL cell lines, which resulted in increased sensitivity to BCL-2 inhibition. Mechanistically, LCK activated NF-xB pathway and the expres-sion of BCL-xL. Silencing ACK1 gene resulted in increased sensitivity to both BCL-2 and BCL-xL inhibitors. ACK1 signaling upregulated AKT pathway, which inhibited the pro-apoptotic function of BAD. In a T-ALL patient-derived xenograft model, combination of NWP-0476 and dasatinib demonstrated synergy without major organ toxicity.Conclusions: LCK and ACK1 signaling pathways are critical regulators of BH3 mimetic resistance in T-ALL. Combination of BH3 mimetics with tyrosine kinase inhibitors might be effective against relapsed T-ALL.
引用
收藏
页码:3151 / 3161
页数:11
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