@article{995ee7f651314684be68e0dc4e007874,
title = "CBP modulates sensitivity to dasatinib in pre-BCR{\th} acute lymphoblastic leukemia",
abstract = "Dasatinib is a multi-tyrosine kinase inhibitor approved for treatment of Ph{\th} 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{\th} 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{\th} 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-BCR{\th} 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.",
author = "Jesus Duque-Afonso and Lin, {Chiou Hong} and Kyuho Han and Morgens, {David W.} and Jeng, {Edwin E.} and Ziming Weng and Johan Jeong and Wong, {Stephen Hon Kit} and Li Zhu and Wei, {Michael C.} and Chae, {Hee Don} and Martin Schrappe and Gunnar Cario and Justus Duyster and Xiangshu Xiao and Sakamoto, {Kathleen M.} and Bassik, {Michael C.} and Cleary, {Michael L.}",
note = "Funding Information: We thank Maria Ambrus and Cita Nicolas for technical assistance, members of the Cleary laboratory for helpful discussions, and Carlos Duque-Afonso for graphic design. This work was supported in part by grants from the NIH (CA214888), the William Lawrence and Blanche Hughes Foundation (to M.L. Cleary), the German Research Foundation (Deutsche Forschungsgemeinschaft, ref. DU 1287/2-1 and 1287/3-1) and Research Commission of the University of Freiburg Medical School (Forschungskommission, ref. DUQ1106/16 to J. Duque-Afonso), the Lucile Packard Foundation for Children's Health, the Child Health Research Institute and the Stanford NIH-NCATS-CTSA grant #UL1 TR001085 (to M.L. Cleary, J. Duque-Afonso, and C.-H. Lin), Alex's Lemonade Stand Foundation for Childhood Cancer (to S.H.K. Wong). K. Han was supported by The Walter V. and Idun Berry Postdoctoral Fellowship Program and M.C. Bassik was supported by a grant from Stanford ChEM-H and an NIH Directors New Innovator Award (1DP2HD08406901). K.M. Sakamoto has been supported by the Maxfield Foundation, SPARK program and Child Health Research Institute Lucile Packard Foundation for Children's Health, Leukemia and Lymphoma Society of America (SLP-8009-15), Pediatric Cancer Research Foundation, Hyundai Hope on Wheels (#02500CA), USC Parker Hughes Institute for Childhood Cancer Research/William Lawrence & Blanche Hughes Foundation, St. Baldrick's Foundation, and Bear Necessities/Rally Foundation. E.E. Jeng was supported by a Hubert Shaw and Sandra Lui Stanford Graduate Fellowship. This material is based on work supported by the National Science Foundation (NSF) Graduate Research Fellowship (grant DGE-114747, to D.W. Morgens). Publisher Copyright: {\textcopyright} 2018 American Association for Cancer Research.",
year = "2018",
month = nov,
day = "15",
doi = "10.1158/0008-5472.CAN-18-1703",
language = "English (US)",
volume = "78",
pages = "6497--6508",
journal = "Cancer Research",
issn = "0008-5472",
number = "22",
}