Abstract
High-risk subtypes of B-cell acute lymphoblastic leukemia (B-ALL) include Philadelphia chromosome-positive (Ph+) B-ALL driven by the BCR-ABL1 oncogene and a more recently identified subtype known as BCR-ABL-like or Ph-like B-ALL. A hallmark of both Ph+ and Ph-like B-ALL is constitutive activation of tyrosine kinase signaling that is potentially targetable with tyrosine kinase inhibitors (TKIs). B-ALL cells also receive extracellular signals from the microenvironment that can maintain proliferation and survival following treatment with TKIs. Therefore, there is strong rationale for combining TKIs with other therapies targeting signal transduction pathways. Here we show that combinations of the ABL-directed TKI dasatinib with mTOR kinase inhibitors (TOR-KIs) are more effective than TKI alone against patient-derived Ph-like B-ALL cells harboring rearrangements of ABL1 or ABL2. We also report the establishment of a new human Ph-like B-ALL cell line that is stromal cell-independent in vitro and can be used for xenograft experiments in vivo. These findings provide rationale for clinical testing of TKI plus TOR-KIs in children and adults with Ph-like B-ALL and a new experimental tool to test promising therapeutic strategies in this poor prognosis subtype of B-ALL.
Highlights
B-lymphoblastic leukemia (B-ALL) is the most common pediatric cancer
Patients with NCI high-risk B-cell acute lymphoblastic leukemia (B-ALL) treated on Children’s Oncology Group (COG) protocols are being tested in real-time for Ph-like ALL-associated alterations and are eligible to participate in clinical trials incorporating dasatinib or ruxolitinib with post-induction chemotherapy (NCT01406756 and NCT02723994) [7]
We previously tested this combination in models of Ph+ B-ALL and found greater anti-leukemia effects when dasatinib was combined with TKI dasatinib with mTOR kinase inhibitors (TOR-KIs) compounds PP242 or MLN0128 [9, 10]
Summary
B-lymphoblastic leukemia (B-ALL) is the most common pediatric cancer. While event-free survival exceeds 85% for most children treated with contemporary therapy, outcomes are very poor for patients who relapse, highlighting a need for further research and new treatments. Patients with NCI high-risk B-ALL treated on Children’s Oncology Group (COG) protocols are being tested in real-time for Ph-like ALL-associated alterations and are eligible to participate in clinical trials incorporating dasatinib or ruxolitinib with post-induction chemotherapy (NCT01406756 and NCT02723994) [7] It is www.impactjournals.com/oncotarget plausible that patients with Ph-like ALL may develop resistance to specific targeted therapies, similar to TKI resistance seen in patients with Ph+ B-ALL, and alternative therapeutic strategies should be explored. We hypothesized that addition of a mammalian target of rapamycin (mTOR) kinase inhibitor (TOR-KI) could prevent this resistance and further decrease overall leukemia burden, as TOR-KIs suppress proliferation and survival signals downstream of both the oncogene and extracellular inputs [8] We previously tested this combination in models of Ph+ B-ALL and found greater anti-leukemia effects when dasatinib was combined with TOR-KI compounds PP242 or MLN0128 [9, 10]. To accelerate further studies of ABL-rearranged Ph-like B-ALL, we describe a novel stroma-independent Ph-like ALL cell line from a child with a somatic ETV6-ABL1 translocation that is suitable for in vitro and in vivo studies
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