Journal
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
Volume 110, Issue 5, Pages 467-478Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/jnci/djx236
Keywords
-
Categories
Funding
- Medical Research Council [G0600782, G0900882, 61568166]
- Kay Kendall Leukaemia Fund [KKL404, KKL501]
- Leuka, Glasgow Experimental Cancer Medicine Centre
- Cancer Research UK
- Chief Scientist's Office (Scotland)
- Cancer Research UK Glasgow Centre [C596/A18076]
- BSU facilities at the Cancer Research UK Beatson Institute [C596/A17196]
- Scottish Universities Life Science Alliance [MSD23_G_Holyoake-Chan]
- Scottish National Blood Transfusion Service
- Cancer Research UK programme [C11074/A11008]
- Howat Foundation and Friends of Paul O'Gorman
- National Cancer Institute grant [CA95111]
- Brain Tumour Charity, Cancer Research UK (CRUK)
- Association for International Cancer Research (AICR)
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- Howard Hughes Medical Institute and National Institutes of Health [R37CA065823]
- Cancer Research UK [11008, 21613, 22903, 15816] Funding Source: researchfish
- Medical Research Council [G0900882, G0600782] Funding Source: researchfish
- Worldwide Cancer Research [13-1083] Funding Source: researchfish
- MRC [G0600782, G0900882] Funding Source: UKRI
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available