Targeting BCR-ABL-Independent TKI Resistance in Chronic Myeloid Leukemia by mTOR and Autophagy Inhibition

被引:80
|
作者
Mitchell, Rebecca [2 ]
Hopcroft, Lisa E. M. [3 ]
Baquero, Pablo [2 ]
Allan, Elaine K. [4 ]
Hewit, Kay [5 ]
James, Daniel [5 ]
Hamilton, Graham [1 ]
Mukhopadhyay, Arunima [3 ]
O'Prey, Jim [5 ]
Hair, Alan [3 ]
Melo, Junia V. [6 ,7 ]
Chan, Edmond [8 ]
Ryan, Kevin M. [5 ]
Maguer-Satta, Veronique [9 ]
Druker, Brian J. [10 ]
Clark, Richard E. [11 ]
Mitra, Subir [12 ]
Herzyk, Pawel [1 ,13 ]
Nicolini, Franck E. [9 ]
Salomoni, Paolo [14 ]
Shanks, Emma [5 ]
Calabretta, Bruno [15 ]
Holyoake, Tessa L. [3 ]
Helgason, G. Vignir [2 ]
机构
[1] Univ Glasgow, Inst Canc Sci, Glasgow Poly, Glasgow, Lanark, Scotland
[2] Univ Glasgow, Inst Canc Sci, Wolfson Wohl Canc Res Ctr, Garscube Estate, Glasgow G61 1QH, Lanark, Scotland
[3] Univ Glasgow, Inst Canc Sci, Paul OGorman Leukaemia Res Ctr, Glasgow, Lanark, Scotland
[4] Gartnavel Royal Hosp, Scottish Natl Blood Transfus Serv, Glasgow, Lanark, Scotland
[5] Beatson Inst, Canc Res UK, Garscube Estate, Glasgow, Lanark, Scotland
[6] Univ Adelaide, Fac Hlth & Med Sci, Adelaide, SA, Australia
[7] Imperial Coll, London, England
[8] Univ Strathclyde, Strathclyde Inst Pharm & Biomed Sci, Glasgow, Lanark, Scotland
[9] Ctr Hosp Lyon Sud, Hematol Clin 1G, Pierre Benite, France
[10] Oregon Hlth & Sci Univ, Knight Canc Inst, Div Hematol & Med Oncol, Portland, OR 97201 USA
[11] Univ Liverpool, Dept Mol & Clin Canc Med, Inst Translat Med, Liverpool, Merseyside, England
[12] Milton Keynes Hosp NHS Fdn Trust, Dept Haematol, Milton Keynes, Bucks, England
[13] Univ Glasgow, Coll Med Vet & Life Sci, Inst Mol Cell & Syst Biol, Glasgow, Lanark, Scotland
[14] UCL Canc Inst, Samantha Dickson Brain Canc Unit, Paul OGorman Bldg, London, England
[15] Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Canc Biol, Philadelphia, PA 19107 USA
来源
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE | 2018年 / 110卷 / 05期
基金
美国国家卫生研究院; 英国医学研究理事会;
关键词
CHRONIC MYELOGENOUS LEUKEMIA; PI3K/MTOR KINASE INHIBITOR; STEM-CELLS; (PI3K)/MAMMALIAN TARGET; MAMMALIAN TARGET; IMATINIB; POTENT; DISCOVERY; PONATINIB; PROTEIN;
D O I
10.1093/jnci/djx236
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: Imatinib and second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib have statistically significantly improved the life expectancy of chronic myeloid leukemia (CML) patients; however, resistance to TKIs remains a major clinical challenge. Although ponatinib, a third-generation TKI, improves outcomes for patients with BCR-ABL-dependent mechanisms of resistance, including the T315I mutation, a proportion of patients may have or develop BCR-ABL-independent resistance and fail ponatinib treatment. By modeling ponatinib resistance and testing samples from these CML patients, it is hoped that an alternative drug target can be identified and inhibited with a novel compound. Methods: Two CML cell lines with acquired BCR-ABL-independent resistance were generated following culture in ponatinib. RNA sequencing and gene ontology (GO) enrichment were used to detect aberrant transcriptional response in ponatinibresistant cells. A validated oncogene drug library was used to identify US Food and Drug Administration-approved drugs with activity against TKI resistant cells. Validation was performed using bone marrow (BM)-derived cells from TKI-resistant patients (n = 4) and a human xenograft mouse model (n =4=6 mice per group). All statistical tests were two-sided. Results: We show that ponatinib-resistant CML cells can acquire BCR-ABL-independent resistance mediated through alternative activation of mTOR. Following transcriptomic analysis and drug screening, we highlight mTOR inhibition as an alternative therapeutic approach in TKI-resistant CML cells. Additionally, we show that catalytic mTOR inhibitors induce autophagy and demonstrate that genetic or pharmacological inhibition of autophagy sensitizes ponatinib-resistant CML cells to death induced by mTOR inhibition in vitro (% number of colonies of control[SD], NVP-BEZ235 vs NVP-BEZ235+1HCQ: 45.0(17.9]% vs 24.0[8.4]%, P =.002) and in vivo (median survival of NVP-BEZ235-vs NVP-BEZ235+HCQ-treated mice: 38.5 days vs 47.0 days, P =.04). Conclusion: Combined mTOR and autophagy inhibition may provide an attractive approach to target BCR-ABL-independent mechanism of resistance.
引用
收藏
页码:467 / 478
页数:12
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