Abstract
Tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of Philadelphia chromosome‐positive acute lymphoblastic leukaemia (Ph+ ALL), one of the most common and aggressive forms of haematological malignancies. However, TKI resistance has remained an unsolved issue. In this study, we investigate the impact of adding arsenic trioxide (ATO) on the action of Dasatinib, a second‐generation TKI, in Ph+ ALL. We show that ATO cooperates with Dasatinib in both TKI‐sensitive and resistant Ph+ ALL cell lines to increase apoptosis and we unravel the underlying mechanisms. Indeed, combining ATO and Dasatinib leads to severe cell apoptosis by activating the UPR apoptotic IRE1/JNK/PUMA axis, while neutralizing the UPR ATF4‐dependent anti‐apoptotic axis, activated by ATO alone. Additionally, ATO and Dasatinib in combination repress the expression of several genes, which we previously showed to be associated with shorter survival probability in ALL patients. Overall these data support the use of ATO in combination with Dasatinib as a novel therapeutic regimen for Ph+ ALL patients.
Highlights
Ph+ ALL accounts for 20–30% of ALL
arsenic trioxide (ATO) was purchased from the First Affiliated Hospital of Harbin Medical University. c-ABL1, Bcl-2, Mcl-1, Noxa and p53 antibodies were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA); b-actin antibody was bought from SigmaAldrich; ERK, p-ERK, STAT5, p-STAT5, PI3K, p-PI3K, AKT, p-AKT, caspase-9, caspase-3, PARP, XIAP, Survivin, Bcl-w, Bik, Bak, Bad, p53-up-regulated modulator of apoptosis (PUMA), Bid, p21, JNK, p-JNK, p-ATF-2, p-JUN, IRE1, ASK1 and ATF4 antibodies were purchased from CST; TRAF2 antibody was purchased from
We demonstrate that ATO combined with Dasatinib trigger apoptosis by simultaneously activating the IRE1/JNK/PUMA apoptosis pathway and inhibiting the ATF4 survival pathway
Summary
The BCR-ABL1 fusion protein, which is encoded by the Ph chromosome, is the main driver of Ph+ ALL. The outcome of Ph+ ALL was very poor until the use of TKIs, which target the kinase domain of the ABL1 moiety and block the catalytic activity of BCR-ABL1. Ph+ ALL patients only exhibit a transient response to a single-agent TKI. In clinical practice, multi-agent chemotherapy needs to be added in combination with TKIs. in clinical practice, multi-agent chemotherapy needs to be added in combination with TKIs Resistance to this treatment has remained an issue and is associated with a high mortality [1]. Accumulated studies point to apoptosis incompetence as a main hallmark of TKI resistance [2, 3]. New strategies should be developed to restore the apoptosis-inducing ability of TKIs
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