Abstract
B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematological disease that kills ~50% of adult patients. With the exception of some BCR-ABL1+ patients who benefit from tyrosine kinase inhibitors, there are no effective targeted therapies for adult B-ALL patients and chemotherapy remains first-line therapy despite adverse side effects and poor efficacy. We show that, although the MEK/ERK pathway is activated in B-ALL cells driven by different oncogenes, MEK inhibition does not suppress B-ALL cell growth. However, MEK inhibition synergized with BCL-2/BCL-XL family inhibitors to suppress proliferation and induce apoptosis in B-ALL cells. We show that this synergism is mediated by the pro-apoptotic factor BIM, which is dephosphorylated as a result of MEK inhibition, allowing it to bind to and neutralize MCL-1, thereby enhancing BCL-2/BCL-XL inhibitor-induced cell death. This cooperative effect is observed in B-ALL cells driven by a range of genetic abnormalities and therefore has significant therapeutic potential.
Highlights
Childhood ALL has good outcomes with 5-year survival rates of ~ 90%, whereas prognosis in older patients (15–65 years; ~ 40% of cases) is worse, with ~ 50% of patients dying from their disease
The MEK/ERK pathway is activated downstream of driver oncogenes such as BCR-ABL1 and NRAS,[6] and we observed different levels of MEK/ERK pathway activation in six B-cell ALL (B-ALL) cell lines expressing BCR-ABL1+ or NRASG12D and in four cell lines driven by other oncoproteins, including ETV6-PDGFRB, ETV6-RUNX1, and MLL-AF4, except RS4;11 cells, which demonstrated no MEK/ ERK pathway activity (Figures 1a and b; Supplementary Figures S1a and b; Supplementary Table S1)
This study demonstrates that MEK inhibitors (MEKi) plus BCL-2/BCL-XL inhibitors (BCL-2i) is a promising drug combination in B-ALL cells
Summary
Childhood ALL has good outcomes with 5-year survival rates of ~ 90%, whereas prognosis in older patients (15–65 years; ~ 40% of cases) is worse, with ~ 50% of patients dying from their disease. The RAS/RAF/MEK/ERK pathway regulates proliferation in haematological malignancies and is activated by mutant RAS or RAF, activated receptor tyrosine kinases such as KIT and FLT3, chromosomal translocations such as BCR-ABL1 or ETV6-PDGFR, or chemotherapeutic agents.[6] Mutations in NRAS, KRAS, and the protein phosphatase PTPN11 are associated with relapse and poorer outcomes in childhood leukemia and with increased sensitivity to MEK inhibitors (MEKi).[7,8] Critically, this pathway regulates survival and apoptosis through ERK-mediated phosphorylation of apoptotic effectors such as BAD and BIM or transcriptional regulation of BCL-2 family genes.[6,9,10]. We reveal a synergistic interaction between two pro-survival pathways that has therapeutic potential in a range of B-ALL subtypes
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