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Cancer Res. 2018 Nov 15;78(22):6497-6508. doi: 10.1158/0008-5472.CAN-18-1703. Epub 2018 Sep 27.

CBP Modulates Sensitivity to Dasatinib in Pre-BCR+ Acute Lymphoblastic Leukemia.

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Department of Pathology, Stanford University School of Medicine, Stanford, California.
Department of Hematology and Oncology, University Medical Center Freiburg, Freiburg, Germany.
Department of Genetics, Stanford University School of Medicine, Stanford, California.
Stanford Center for Genomics and Personalized Medicine, Stanford, California.
Department of Pediatrics, Stanford University School of Medicine, Stanford, California.
Department of Pediatrics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon.
Department of Pathology, Stanford University School of Medicine, Stanford, California.
Contributed equally


Dasatinib is a multi-tyrosine kinase inhibitor approved for treatment of Ph+ acute lymphoblastic leukemia (ALL), but its efficacy is limited by resistance. Recent preclinical studies suggest that dasatinib may be a candidate therapy in additional ALL subtypes including pre-BCR+ ALL. Here we utilized shRNA library screening and global transcriptomic analysis to identify several novel genes and pathways that may enhance dasatinib efficacy or mitigate potential resistance in human pre-BCR+ ALL. Depletion of the transcriptional coactivator CBP increased dasatinib sensitivity by downregulating transcription of the pre-BCR signaling pathway previously associated with dasatinib sensitivity. Acquired resistance was due, in part, to upregulation of alternative pathways including WNT through a mechanism, suggesting transcriptional plasticity. Small molecules that disrupt CBP interactions with the CREB KID domain or β-catenin showed promising preclinical efficacy in combination with dasatinib. These findings highlight novel modulators of sensitivity to targeted therapies in human pre-BCR+ ALL, which can be reversed by small-molecule inhibitors. They also identify promising therapeutic approaches to ameliorate dasatinib sensitivity and prevent resistance in ALL.Significance: These findings reveal mechanisms that modulate sensitivity to dasatinib and suggest therapeutic strategies to improve the outcome of patients with acute lymphoblastic leukemia.Graphical Abstract: Cancer Res; 78(22); 6497-508. ©2018 AACR.

[Available on 2019-11-15]

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