A therapeutically targetable mechanism of BCR-ABL-independent imatinib resistance in chronic myeloid leukemia

• Type of Material: Article
• Authors: Leyuan Ma, University of Massachusetts; Yi Shan, University of Massachusetts; Robert Bai, University of Massachusetts; Liting Xue, University of Massachusetts; Christopher A. Eide, Oregon Health and Science University; Jianhong Ou, University of Massachusetts; Lihua J. Zhu, University of Massachusetts; Lloyd Hutchinson, University of Massachusetts; Jan Cerny, University of Massachusetts; Hanna Khoury, Emory University; Zhi Sheng, Virginia Tech Carilion Research Institute; Brian J. Druker, Oregon Health and Science University; Shaoguang Li, University of Massachusetts; Michael R. Green, University of Massachusetts
• Language: English
• Date: 2014-09-03
• Publisher: American Association for the Advancement of Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014, American Association for the Advancement of Science. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1126/scitranslmed.3009073
• Title of Journal or Parent Work: Science Translational Medicine
• ISSN: 1946-6234
• Volume: 6
• Issue: 252
• Start Page: 252ra121
• End Page: 252ra121
• Grant/Funding Information: The research was supported in part by funds from the Georgia Cancer Coalition.; This work was supported by a grant from the National Institutes of Health (R01 CA163926) to M.R.G.; R.B. is a Howard Hughes Medical Institute Medical Research Fellow.; B.J.D. is a Howard Hughes Medical Institute Investigator and receives additional research funding from NIH MERIT award 5R37 CA65823-16 and the Leukemia & Lymphoma Society.
• Keywords: Research & Experimental Medicine; ACTIVATES RAF-1; PATHWAY; MAMMARY-GLAND; PHILADELPHIA-CHROMOSOME; Medicine, Research & Experimental; CHRONIC MYELOGENOUS LEUKEMIA; HEMATOPOIETIC-CELLS; STEM-CELLS; Science & Technology; KINASE-C ISOTYPES; Life Sciences & Biomedicine; PROTEIN-KINASE; Cell Biology; MESYLATE
• Research Categories: Health Sciences, Oncology; Health Sciences, Medicine and Surgery

Abstract

Resistance to the BCR-ABL inhibitor imatinib mesylate (IM) poses a major problem for the treatment of chronic myeloid leukemia (CML). IM resistance often results from a secondary mutation in BCR-ABL that interferes with drug binding. However, in many instances, there is no mutation in BCR-ABL, and the basis of such BCR-ABL-independent IM resistance remains to be elucidated. To gain insight into BCR-ABL-independent IM resistance mechanisms, we performed a large-scale RNA interference screen and identified IM-sensitizing genes (IMSGs) whose knockdown renders BCR-ABL+ cells IM-resistant. In these IMSG knockdown cells, RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling is sustained after IM treatment because of upregulation of PRKCH, which encodes the protein kinase C (PKC) family member PKCh, an activator of CRAF. PRKCH is also up-regulated in samples from CML patients with BCR-ABL-independent IM resistance. Combined treatment with IM and trametinib, a U.S. Food and Drug Administration-approved MEK inhibitor, synergistically kills BCR-ABL+ IMSG knockdown cells and prolongs survival in mouse models of BCR-ABL-independent IM-resistant CML. Finally, we showed that CML stem cells contain high levels of PRKCH, and this contributes to their intrinsic IM resistance. Combined treatment with IM and trametinib synergistically kills CML stem cells with negligible effect on normal hematopoietic stem cells. Collectively, our results identify a therapeutically targetable mechanism of BCR-ABL-independent IM resistance in CML and CML stem cells.