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



Mitchell, Rebecca, Hopcroft, Lisa EM, Baquero, Pablo, Allan, Elaine K, Hewit, Kay, James, Daniel, Hamilton, Graham, Mukhopadhyay, Arunima, O'Prey, Jim, Hair, Alan
et al (show 14 more authors) (2018) Targeting BCR-ABL-Independent TKI Resistance in Chronic Myeloid Leukemia by mTOR and Autophagy Inhibition. JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 110 (5). 467 - 478.

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Abstract

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 ponatinib-resistant 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+HCQ: 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.

Item Type: Article
Uncontrolled Keywords: trasnscription, genetic, leukemia, myelocitic, chronic, autophagy, catalysis, cell lines, genes, mice, pharmacology, imatinib mesylate, protein-tyrosine kinase inhibitor, dasatinib, mtor serine-threonine kinases, mtor inhibitors, ponatinib
Depositing User: Symplectic Admin
Date Deposited: 04 Feb 2019 12:00
Last Modified: 26 Nov 2021 01:11
DOI: 10.1093/jnci/djx236
Open Access URL: https://doi.org/10.1093/jnci/djx236
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3032240