Overcoming Drug-resistance in Chronic Myeloid Leukemia

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dc.contributor Helsingin yliopisto, Lääketieteellinen tiedekunta fi
dc.contributor University of Helsinki, Faculty of Medicine en
dc.contributor Helsingfors universitet, Medicinska fakulteten sv
dc.contributor.author Rebane, Anni
dc.date.issued 2015
dc.identifier.uri URN:NBN:fi:hulib-201801191074
dc.identifier.uri http://hdl.handle.net/10138/231375
dc.description.abstract Given the success of first-line treatment in chronic myeloid leukemia (CML), the prevalence of the disease is estimated to increase and more patients are expected to develop resistance to therapy. Thus, even relatively rare point mutations are likely to become more common. In CML, the uncontrollable division of myeloid cells is caused by a reciprocal translocation of chromosomes 9 and 22, resulting in the Philadelphia chromosome. At the meeting point of the two chromosomes, breakpoint cluster region (BCR) and Abelson proto-oncogene 1 (ABL1) fuse together to form the chimeric fusion oncogene BCR-ABL1, the latter of which, the non-receptor tyrosine kinase ABL1, is the driver of the disease. Since the tyrosine kinase inhibitor (TKI) imatinib became available in 2001, the success of first-line therapy has significantly improved the prognosis of CML patients. However, up to 50% of patients with imatinib-refractory disease develop resistance due to point mutations in ABL1, and the most common mutation to emerge is BCR-ABL1 T315I. The broad-range TKI ponatinib is the only approved TKI that inhibits the kinase activity of BCR-ABL1 T315I, but adverse side effects leave patients with this mutation in need of a better, safer, and more effective treatment. The kinase inhibitor axitinib was shown to be selective for BCR-ABL1 T315I, but mutations that emerge as a consequence of axitinib-resistance have yet to be explored. Moreover, patients with the T315I mutation treated with ponatinib have been reported to develop highly drug-resistant mutations in BCR-ABL1 such as T315M and the E255V/T315I compound mutation. The purpose of this study was to identify mutations that enable cells to develop resistance to the kinase inhibitor axitinib and to find new, potential inhibitors for cells expressing the drug-resistant mutations BCR-ABL1 T315I, BCR-ABL1 T315M, and BCR-ABL1 E255V/T315I. To this end, mouse hematopoietic cell lines were constructed prior to determining cell viability in response to inhibitors in combinations and as independent agents. As a novel finding, cells stably expressing T315M were found to exhibit sensitivity to inhibitors of topoisomerase II and mTOR. Moreover, synthetic lethality occurred in these cells in response to the combined treatment of the allosteric inhibitor asciminib and the TKI ponatinib, although not in clinically relevant doses. The highly resistant cells expressing BCR-ABL1 E255V/T315I, like cells expressing T315I and T315M, showed sensitivity to conventional chemotherapy. Notably, however, three SMAC mimetics displayed selectivity to cells expressing BCR-ABL1 E255V/T315I over cells expressing only the single T315I mutation. Considering that CML is expected to become increasingly prevalent, more patients are estimated to develop resistance to therapy. As even relatively rare mutations in BCR-ABL1 become more common, finding an effective treatment for cells expressing these highly resistant mutations takes us one step closer to identifying a safe and effective treatment for CML patients carrying those mutations. en
dc.language.iso eng
dc.publisher Helsingin yliopisto fi
dc.publisher University of Helsinki en
dc.publisher Helsingfors universitet sv
dc.subject BCR-ABL1
dc.subject T315I
dc.subject T315M
dc.subject E255V/T315I
dc.subject Chronic myeloid leukemia en
dc.subject CML en
dc.subject leukemia en
dc.subject drug-resistance en
dc.subject point mutations en
dc.subject high-throughput screening en
dc.subject combination testing en
dc.title Overcoming Drug-resistance in Chronic Myeloid Leukemia en
dc.type.ontasot pro gradu -tutkielmat fi
dc.type.ontasot master's thesis en
dc.type.ontasot pro gradu-avhandlingar sv
dc.subject.discipline Cancer en
dct.identifier.urn URN:NBN:fi:hulib-201801191074

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