MEK1/2 regulate normal BCR and ABL1 tumor-suppressor functions to dictate ATO response in TKI-resistant Ph+ leukemia

Autor: Mazzera, Laura, Abeltino, Manuela, Lombardi, Guerino, Cantoni, Anna Maria, Jottini, Stefano, Corradi, Attilio, Ricca, Micaela, Rossetti, Elena, Armando, Federico, Peli, Angelo, Ferrari, Anna, Martinelli, Giovanni, Scupoli, Maria Teresa, Visco, Carlo, Bonifacio, Massimiliano, Ripamonti, Alessia, Gambacorti-Passerini, Carlo, Bonati, Antonio, Perris, Roberto, Lunghi, Paolo
Zdroj: Leukemia; August 2023, Vol. 37 Issue: 8 p1671-1685, 15p
Abstrakt: Resistance to tyrosine kinase inhibitors (TKIs) remains a clinical challenge in Ph-positive variants of chronic myeloid leukemia. We provide mechanistic insights into a previously undisclosed MEK1/2/BCR::ABL1/BCR/ABL1-driven signaling loop that may determine the efficacy of arsenic trioxide (ATO) in TKI-resistant leukemic patients. We find that activated MEK1/2 assemble into a pentameric complex with BCR::ABL1, BCR and ABL1 to induce phosphorylation of BCR and BCR::ABL1 at Tyr360 and Tyr177, and ABL1, at Thr735 and Tyr412 residues thus provoking loss of BCR’s tumor-suppression functions, enhanced oncogenic activity of BCR::ABL1, cytoplasmic retention of ABL1 and consequently drug resistance. Coherently, pharmacological blockade of MEK1/2 induces dissociation of the pentameric MEK1/2/BCR::ABL1/BCR/ABL1 complex and causes a concurrent BCRY360/Y177, BCR::ABL1Y360/Y177and cytoplasmic ABL1Y412/T735dephosphorylation thereby provoking the rescue of the BCR’s anti-oncogenic activities, nuclear accumulation of ABL1 with tumor-suppressive functions and consequently, growth inhibition of the leukemic cells and an ATO sensitization via BCR-MYC and ABL1-p73 signaling axes activation. Additionally, the allosteric activation of nuclear ABL1 was consistently found to enhance the anti-leukemic effects of the MEK1/2 inhibitor Mirdametinib, which when combined with ATO, significantly prolonged the survival of mice bearing BCR::ABL1-T315I-induced leukemia. These findings highlight the therapeutic potential of MEK1/2-inhibitors/ATO combination for the treatment of TKI-resistant leukemia.
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