Credit: Sarah Pfau
Researchers have devised a strategy that leverages autophagy to work against multiple myeloma (MM).
Their method involves targeting the p62 protein, which plays a role in disposing of unwanted cellular proteins during autophagy.
The team used anticancer agents to induce autophagy in MM cells and found that simultaneously blocking p62 expression, either pharmacologically or with shRNA, could prompt apoptosis in the cells, both in vitro and in vivo.
Steven Grant, MD, of Virginia Commonwealth University’s Massey Cancer Center, and his colleagues described this work in Molecular and Cellular Biology.
“Therapies that are designed to block the early stages of autophagy do not offer the possibility of exploiting its potentially lethal effects,” Dr Grant said. “Our strategy turns autophagy from a protective process into a toxic one, and these results suggest it could increase the effectiveness of a variety of cancer therapies that induce autophagy.”
The researchers conducted several experiments in MM cell lines and mouse models of the disease. They used an anticancer agent—obatoclax or bortezomib—to induce autophagy and a cyclin-dependent kinase (CDK) inhibitor—flavopiridol or dinaciclib—or shRNA to target p62.
And they discovered that blocking p62 disrupted autophagy and killed far more MM cells than administering anticancer agents alone.
Critical to the success of this strategy is Bik, a protein that plays a significant role in governing cell death and survival. With anticancer treatment, Bik accumulates in MM cells until it triggers apoptosis.
Normally, the MM cells would initiate autophagy to survive, and p62 would rid the cells of Bik by loading the proteins into autophagosomes for disposal.
However, the researchers found that blocking p62 production results in an inefficient form of autophagy, and the accumulation of Bik eventually causes the MM cells to undergo apoptosis.
This research builds upon more than a decade of work by Dr Grant’s lab, in which the team investigated novel treatment strategies and combination therapies that selectively kill MM cells and other blood cancer cells.
“We are now working to identify additional CDK inhibitors that can be used to disrupt autophagy,” Dr Grant said. “The ultimate goal will be to translate these findings into a clinical trial to test the therapy in patients with various blood cancers.”
The technology in his study has been made available for licensing through the Virginia Commonwealth University Office of Research.
