PBA2, a novel inhibitor of imatinib-resistant BCR-ABL T315I mutation in chronic myeloid leukemia

Pranav Gupta, Rishil J. Kathawala, Liuya Wei, Fang Wang, Xiao Kun Wang, Brian Druker, Li Wu Fu, Zhe Sheng Chen

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Chronic Myeloid Leukemia (CML) is largely caused by the Philadelphia (Ph) chromosome carrying the Break point Cluster Region-Abelson (BCR-ABL) oncogene. Imatinib is a BCR-ABL-targeted therapy and considered the standard of care in CML management. Resistance to imatinib therapy often develops because of mutations in the BCR-ABL kinase domain. In this study, we evaluated PBA2, a novel BCR-ABL inhibitor, for its anti-cancer activity against BCR-ABL expressing BaF3 cells. PBA2 shows potent activity against wild-type and T315I mutated BaF3 cells as compared with imatinib. PBA2 inhibited the phosphorylation of BCR-ABL and its downstream signaling in BaF3/WT and BaF3/T315I cells. PBA2 inhibited the mRNA expression of BCR-ABL in BaF3/WT and BaF3/T315I cells. Mechanistically, PBA2 increased the cell population in sub G1 phase of the cell cycle, induced apoptosis and elevated ROS production in both BaF3/WT and BaF3/T315I cells. Taken together, our results indicate that PBA2 exhibits anti-proliferative effects and inhibits the imatinib-resistant T315I BCR-ABL mutation. PBA2 may be a novel drug candidate for overcoming the resistance to imatinib in CML patients.

Original languageEnglish (US)
Pages (from-to)220-229
Number of pages10
JournalCancer Letters
Volume383
Issue number2
DOIs
StatePublished - Dec 28 2016

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Mutation
Chromosome Breakage
Philadelphia Chromosome
G1 Phase
Standard of Care
Oncogenes
Imatinib Mesylate
Cell Cycle
Phosphotransferases
Phosphorylation
Apoptosis
Messenger RNA
Therapeutics
Pharmaceutical Preparations
Population
Neoplasms

Keywords

  • BCR-ABL
  • Chronic myeloid leukemia
  • PBA2
  • Resistance
  • T315I

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

PBA2, a novel inhibitor of imatinib-resistant BCR-ABL T315I mutation in chronic myeloid leukemia. / Gupta, Pranav; Kathawala, Rishil J.; Wei, Liuya; Wang, Fang; Wang, Xiao Kun; Druker, Brian; Fu, Li Wu; Chen, Zhe Sheng.

In: Cancer Letters, Vol. 383, No. 2, 28.12.2016, p. 220-229.

Research output: Contribution to journalArticle

Gupta, P, Kathawala, RJ, Wei, L, Wang, F, Wang, XK, Druker, B, Fu, LW & Chen, ZS 2016, 'PBA2, a novel inhibitor of imatinib-resistant BCR-ABL T315I mutation in chronic myeloid leukemia', Cancer Letters, vol. 383, no. 2, pp. 220-229. https://doi.org/10.1016/j.canlet.2016.09.025
Gupta, Pranav ; Kathawala, Rishil J. ; Wei, Liuya ; Wang, Fang ; Wang, Xiao Kun ; Druker, Brian ; Fu, Li Wu ; Chen, Zhe Sheng. / PBA2, a novel inhibitor of imatinib-resistant BCR-ABL T315I mutation in chronic myeloid leukemia. In: Cancer Letters. 2016 ; Vol. 383, No. 2. pp. 220-229.
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