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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.

Author information

1
Department of Pathology, Stanford University School of Medicine, Stanford, California.
2
Department of Hematology and Oncology, University Medical Center Freiburg, Freiburg, Germany.
3
Department of Genetics, Stanford University School of Medicine, Stanford, California.
4
Stanford Center for Genomics and Personalized Medicine, Stanford, California.
5
Department of Pediatrics, Stanford University School of Medicine, Stanford, California.
6
Department of Pediatrics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.
7
Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon.
8
Department of Pathology, Stanford University School of Medicine, Stanford, California. mcleary@stanford.edu.
#
Contributed equally

Abstract

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: http://cancerres.aacrjournals.org/content/canres/78/22/6497/F1.large.jpg Cancer Res; 78(22); 6497-508. ©2018 AACR.

PMID:
30262461
PMCID:
PMC6283070
[Available on 2019-11-15]
DOI:
10.1158/0008-5472.CAN-18-1703

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