Examining a new class of dual CDC7/CDK9 inhibitors, mechanisms of proliferation, and proliferation-based stratification in myeloma
Coyne, Mark Robert
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A key feature of progressive myeloma is a relative increase in proliferation. The DBF4-dependent kinase (DDK), cell division cycle 7 (CDC7), is an essential kinase for initiation of DNA replication. This thesis assesses the activity of the prototype CDC7 inhibitor PHA-767491 and its bioavailable related compound, NMS-354, in pre-clinical models of myeloma. Both such inhibitors are characterised as dual CDC7/CDK9 inhibitors. The thesis finds first that PHA-767491 and NMS-354 demonstrate efficacy in pre-clinical cell-based myeloma and stem cell models. Secondly, CDC7/CDK9 inhibition is found to be additive to melphalan, bortezomib, and doxorubicin in myeloma cell lines. The combination of p38 MAPK and CDC7/CDK9 inhibitors is, unexpectedly, potently synergistic. CDC7/CDK9 inhibition activates MK2, a downstream target of the p38 MAPK pathway. However, thirdly, preliminary experiments did not reveal activity of NMS-354 in the Vk*MYC myeloma mouse models. Fourthly, DBF4 is found to be the main regulator of CDC7 in malignant and non-malignant plasma cells. DBF4 overexpression predicts an inferior overall survival and time to progression in newly diagnosed myeloma patients, but fails to reach independence from the gene-expression-based proliferation index on multivariate analysis. Dual staining with CD138, a plasma cell marker, and pMCM2 proves to be more predictive of plasma cell labeling index than the MIB index and gene expression-based proliferation indices. Finally, this thesis finds that the G2/M DNA damage checkpoint is the most important canonical pathway enriched in patients with a high proliferation index across TC myeloma groups. Through the analysis of these various elements, this thesis examines the role of proliferation as a therapeutic strategy as well as a stratifier in myeloma, through examination of the DDK, CDC7.
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