Credit: VCU
The experimental drug dinaciclib could potentially improve the treatment of multiple myeloma (MM) and myeloid leukemias, according to preclinical research published in Molecular Cancer Therapeutics.
The study showed that dinaciclib disrupts a cell survival mechanism known as the unfolded protein response (UPR).
And without the UPR, MM and myeloid leukemia cells were unable to combat damage caused by anticancer agents that induce stress in the endoplasmic reticulum (ER).
“Although dinaciclib has shown promising preclinical activity against a variety of tumor cells and is currently undergoing phase 1/2 clinical trials in several malignancies, the mechanisms responsible for its antitumor activity are not fully understood,” said study author Steven Grant, MD, of the Virginia Commonwealth University Massey Cancer Center.
“Our research highlights a potentially new mechanism of dinaciclib action and raises the possibility that this agent could be a useful addition to current multiple myeloma and myeloid leukemia therapies.”
Dinaciclib is a cyclin-dependent kinase (CDK) inhibitor. CDKs are overactive in many cancers, which results in unregulated proliferation of cancer cells.
Observations from this study suggest that 2 specific CDKs, CDK1 and CDK5, play key roles in regulating the UPR by helping to control the production and accumulation of X-box binding pretein-1 (XBP-1). The spliced form of XBP-1 (XBP-1s) helps regulate the expression of genes critical to cellular stress responses.
External stressors, including certain anticancer agents, can cause misfolded proteins to accumulate in the ER. These stressors can also cause XBP-1s to accumulate in the cell’s nucleus, which promotes the UPR and helps cells withstand the damaging effects of misfolded proteins.
This research showed that dinaciclib, by interfering with UPR activation, caused MM and myeloid leukemia cells to initiate apoptosis when exposed to thapsigargin and tunicamycin—2 agents that induce ER stress.
And single-agent dinaciclib treatment significantly decreased tumor growth in mouse models of MM, when compared to vehicle control.
“These findings build on a long history of work in our laboratory investigating mechanisms by which cancer cells respond to environmental stresses,” Dr Grant said.
“We intend to continue investigating ways in which dinaciclib and other CDK inhibitors might be used to disrupt the UPR and potentially improve the effectiveness of certain agents for the treatment of multiple myeloma or myeloid leukemia.”
