Abstract
Two key features of myeloma cells are the deregulation of the cell cycle and the dependency on the expression of the BCL2 family of anti-apoptotic proteins. The cell division cycle 7 (CDC7) is an essential S-phase kinase and emerging CDC7 inhibitors are effective in a variety of preclinical cancer models. These compounds also inhibit CDK9 which is relevant for MCL-1 expression. The activity and mechanism of action of the dual CDC7/CDK9 inhibitor PHA-767491 was assessed in a panel of multiple myeloma cell lines, in primary samples from patients, in the presence of stromal cells and in combination with drugs used in current chemotherapeutic regimens. We report that in all conditions myeloma cells undergo cell death upon PHA-767491 treatment and we report an overall additive effect with melphalan, bortezomib and doxorubicin, thus supporting further assessment of targeting CDC7 and CDK9 in multiple myeloma.
Highlights
Myeloma is a post-germinal B-cell malignancy and the second most common hematological cancer [1]
In order to understand how myeloma cells respond to cell division cycle 7 (CDC7)/cyclin dependent kinase 9 (CDK9) dual inhibition, we initially challenged a panel of human myeloma cell lines with the prototype CDC7/CDK9 inhibitor, PHA-767491
Using an ATP-based cell-viability assay, we found that cell viability was lost at low micromolar levels of PHA-767491 in all cell lines with IC50 values spanning from 1 to 3.5 μM (Table 1)
Summary
Myeloma is a post-germinal B-cell malignancy and the second most common hematological cancer [1]. CDC7 depletion, in contrast to replication fork blockade, does not cause a sustained activation of the DNA damage response (DDR) which is a common feature of chemotherapeutics that target DNA replication [16] These characteristics have led to the development of small molecule inhibitors of the CDC7 kinase with the most advanced currently in phase I clinical studies [17,18]. In this study we assessed the activity of PHA-767491 in several cellular models of multiple myeloma including established and primary cell lines and in a co-culture system that partially mimic the bone marrow microenvironment and provides protection against chemotherapeutic drugs currently used in the treatment of this disease [27,28,29] In these contexts we find that the drug causes cell death and has the potential to overcome the activation of survival signaling pathways
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