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 language | English (US) |
|---|---|
| Pages (from-to) | 6497-6508 |
| Number of pages | 12 |
| Journal | Cancer Research |
| Volume | 78 |
| Issue number | 22 |
| DOIs | |
| State | Published - Nov 15 2018 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
CBP modulates sensitivity to dasatinib in pre-BCRþ acute lymphoblastic leukemia. / Duque-Afonso, Jesus; Lin, Chiou Hong; Han, Kyuho; Morgens, David W.; Jeng, Edwin E.; Weng, Ziming; Jeong, Johan; Wong, Stephen Hon Kit; Zhu, Li; Wei, Michael C.; Chae, Hee Don; Schrappe, Martin; Cario, Gunnar; Duyster, Justus; Xiao, Xiangshu; Sakamoto, Kathleen M.; Bassik, Michael C.; Cleary, Michael L.
In: Cancer Research, Vol. 78, No. 22, 15.11.2018, p. 6497-6508.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - CBP modulates sensitivity to dasatinib in pre-BCRþ acute lymphoblastic leukemia
AU - Duque-Afonso, Jesus
AU - Lin, Chiou Hong
AU - Han, Kyuho
AU - Morgens, David W.
AU - Jeng, Edwin E.
AU - Weng, Ziming
AU - Jeong, Johan
AU - Wong, Stephen Hon Kit
AU - Zhu, Li
AU - Wei, Michael C.
AU - Chae, Hee Don
AU - Schrappe, Martin
AU - Cario, Gunnar
AU - Duyster, Justus
AU - Xiao, Xiangshu
AU - Sakamoto, Kathleen M.
AU - Bassik, Michael C.
AU - Cleary, Michael L.
PY - 2018/11/15
Y1 - 2018/11/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85056577080&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85056577080&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-18-1703
DO - 10.1158/0008-5472.CAN-18-1703
M3 - Article
VL - 78
SP - 6497
EP - 6508
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 22
ER -