CBP modulates sensitivity to dasatinib in pre-BCRþ acute lymphoblastic leukemia

Jesus Duque-Afonso, Chiou Hong Lin, Kyuho Han, David W. Morgens, Edwin E. Jeng, Ziming Weng, Johan Jeong, Stephen Hon Kit Wong, Li Zhu, Michael C. Wei, Hee Don Chae, Martin Schrappe, Gunnar Cario, Justus Duyster, Xiangshu Xiao, Kathleen M. Sakamoto, Michael C. Bassik, Michael L. Cleary

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Dasatinib is a multi-tyrosine kinase inhibitor approved for treatment of Phþ 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-BCRþ 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-BCRþ 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 b-catenin showed promising preclinical efficacy in combination with dasatinib. These findings highlight novel modulators of sensitivity to targeted therapies in human pre-BCRþ 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.

Original languageEnglish (US)
Pages (from-to)6497-6508
Number of pages12
JournalCancer Research
Volume78
Issue number22
DOIs
StatePublished - Nov 15 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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