American Association for Cancer Research
ccr-23-0415_supplementary_figures_1-9_suppfs1-9.pdf (2.18 MB)

Supplementary figures 1-9 from Dual Targeting of Apoptotic and Signaling Pathways in T-Lineage Acute Lymphoblastic Leukemia

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journal contribution
posted on 2023-08-15, 08:20 authored by Caner Saygin, Giorgia Giordano, Kathryn Shimamoto, Bart Eisfelder, Anika Thomas-Toth, Girish Venkataraman, Vijayalakshmi Ananthanarayanan, Tiffaney L. Vincent, Adam DuVall, Anand A. Patel, Yi Chen, Fenlai Tan, Stephen P. Anthony, Yu Chen, Yue Shen, Olatoyosi Odenike, David T. Teachey, Barbara L. Kee, James LaBelle, Wendy Stock

Supplementary Figures 1-9


Leukemia and Lymphoma Society (LLS)

American Society of Hematology (ASH)

Conquer Cancer Foundation (CCF)

Prevent Cancer Foundation (PCF)

Cancer Research Foundation (CRF)



Relapsed T-acute lymphoblastic leukemia (T-ALL) has limited treatment options. We investigated mechanisms of resistance 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. 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. 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 pathways 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-κB pathway and the expression 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. 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.

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