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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • CREB-Binding Protein / metabolism*
  • Cell Cycle
  • Cell Line, Tumor
  • Dasatinib / pharmacology*
  • Drug Resistance, Neoplasm*
  • Drug Screening Assays, Antitumor
  • Gene Expression Regulation, Leukemic
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Protein Binding
  • Protein Domains
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / pharmacology
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Transcription, Genetic
  • beta Catenin / genetics

Substances

  • Antineoplastic Agents
  • CTNNB1 protein, human
  • Protein Kinase Inhibitors
  • Pyrimidines
  • RNA, Small Interfering
  • beta Catenin
  • CREB-Binding Protein
  • CREBBP protein, human
  • Dasatinib