Researchers at Duke University have shown that blocking an enzyme involved in iron regulation not only kills multiple myeloma cancer cells, but also increases the effectiveness of current therapies against the disease.
The research appeared September 12 in the journal Blood.
Multiple myeloma (MM) is an incurable cancer of plasma, a type of white blood cell that normally makes antibodies to fight infection. MM cells build up in the bone marrow, crowding out healthy blood-forming cells, and produce large amounts of abnormal antibodies. This buildup can weaken the immune system, damage the kidneys and other organs, and cause painful bone disease. MM accounts for nearly 10 percent of all blood cancer diagnoses, and while there are targeted treatments to manage the disease, incidences of symptom relapse and drug-resistant multiple myeloma are increasing.
Although it's unclear what causes multiple myeloma, researchers have observed that MM is often associated with the suppression of ferroptosis, a natural process of cell death associated with excess iron accumulation. Ferroptosis causes oxidative damage to the lipids in the cellular membrane, triggering the cell to break apart. But when that process is suppressed, cell death doesn't occur.
"Cancer cells live like there is no tomorrow," said Mikhail Nikiforov, professor of pathology and biomedical engineering at Duke. "They accumulate iron at levels that would normally be toxic and tear cells apart, but that wasn't what we observed. Instead, these cancer cells adapted to resist the type of cell death triggered by iron overload, and the mechanisms behind this suppression were largely unknown."
But Nikiforov and a team of collaborators across Duke have finally answered this long-standing question by identifying kinase STK17B as a key enzyme responsible for suppressing ferroptosis in MM cells. Typically involved in cell death and T-cell activation, the researchers observed that STK17B was also critical at maintaining the balance of iron in the cell by regulating pro- and anti-ferroptotic proteins.
"Elevated levels of STK17B are associated with poor overall survival in MM patients," said Nikiforov. "STK17B expression is also especially pronounced in relapsed cases of the disease, underscoring its role in therapy resistance."
Using a compound developed by Timothy Willson, the Harold Kohn Distinguished Professor in Open Science Drug Discovery at the UNC Eshelman School of Pharmacy, the team was able to inhibit STK17B's control over iron buildup in the cell, reactivating ferroptosis. They also observed that inhibiting STK17B made cancer cells more sensitive to conventional MM therapies.
As a proof of concept, Nikiforov's team administered an oral version of the inhibitor to MM mouse models. They observed that the compound both induced ferroptosis by increasing the iron uptake of cancer cells and significantly reduced tumor growth in the mouse models.
"These findings establish that STK17B is a critical safeguard protecting MM cells from the toxic consequences of their iron independence," said Nikiforov. "Inhibiting this kinase holds much promise as a therapeutic strategy."
Beyond plans to explore how to improve the formulation, the team has also filed a provisional patent based on their findings with the goal of eventually commercializing the therapy. They also hope to study how the formula could be used to regulate drug resistance in other cancers.
"Many other types of cancer cells are also resistant to ferroptosis," said Nikiforov. "We're curious to see how this inhibitor could improve therapies for other tumors outside of multiple myeloma."
This work was supported by the National Institutes of Health, the National Cancer Institute grants NCI R01CA264984 (M.A.N), NCI R21CA267275 and 17R21CA280499 (Y. K.), NHLBI R01HL168492 (E.A.L.), NCI P30CA014236 (Duke Cancer Institute), and support from the Paula and Rodger Riney Foundation (L.H.B.). The Structural Genomics Consortium (SGC) is a registered charity (no: 1097737) that receives funds from Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Genome Canada, through Ontario Genomics Institute [OGI-196], EU/EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative 2 Joint Under-taking [EUbOPEN grant 875510], Janssen, Merck KGaA (also known as EMD in Canada and the US), Pfizer, and Takeda. Funding for this project was provided in part by the NIH Illuminating the Druggable Genome grant 1U24DK116204-01.