Effective concentration of a multi-kinase inhibitor within bone marrow correlates with in vitro cell killing in therapy-resistant chronic myeloid leukemia

Chaofeng Mu, Xiaoyan Wu, Helen Ma, Wenjing Tao, Guodong Zhang, Xiaojun Xia, Jianliang Shen, Junhua Mai, Tong Sun, Xiaoping Sun, Ralph B Arlinghaus, Haifa Shen

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Leukemia cells escape BCR-ABL-targeted therapy by developing mutations such as T315I in the p210BCR-ABL fusion protein in Philadelphia chromosome-positive chronic myeloid leukemia (CML). While most effort has been focused on development of new tyrosine kinase inhibitors (TKIs), enrichment of these small molecule inhibitors in the tumor tissue can also have a profound impact on treatment outcomes. Here, we report that a 2-hour exposure of the T315I mutant CML cells to 10 μM of the multi-kinase inhibitor TG101209 suppressed BCR-ABL-independent signaling and caused cell cycle arrest at G2/M. Further increase in drug concentration to 17.5 μM blocked phosphorylation of the mutant BCR-ABL kinase and its downstream JAK2 and STAT5. The effective dosage to overcome therapy resistance identified in an in vitro setting serves as a guidance to develop the proper drug formulation for in vivo efficacy. A targeted formulation was developed to achieve sustained bone marrow TG101209 concentration at or above 17.5 μM for effective killing of CML cells in vivo. Potent inhibition of leukemia cell growth and extended survival were observed in two murine models of CML treated with 40 mg/kg intravenously administered targeted TG101209, but not with the untargeted drug at the same dosage. Our finding provides a unique approach to develop treatments for therapy-resistant CML.

Original languageEnglish (US)
JournalMolecular Cancer Therapeutics
DOIs
StateE-pub ahead of print - Feb 4 2016

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