A Children’s Hospital of Philadelphia (CHOP) oncology research team reports that a well-known gene that normally drives cancer could potentially benefit cancer patients if used in combination with chemotherapy. The laboratory team found this seeming paradox in both human cancer cells and in mouse models.
“This study is a reminder of the complexity of cancer,” said study leader Andrei Thomas-Tikhonenko, PhD. “Many cancer researchers have focused on silencing the oncogene MYC, but we found that the Myc protein produced by this gene makes chemotherapy drugs more efficient in killing cancer cells.” Thomas-Tikhonenko and colleagues published their research online March 26, 2019, in the journal Leukemia. The team investigated Burkitt lymphoma, a cancer of the lymphatic system that occurs in both children and adults.
Because the MYC oncogene is active in about half of human cancers, the finding could be relevant to other MYC-driven cancers in addition to Burkitt lymphoma, said first author Colleen T. Harrington, who started working on this project in close collaboration with Elena Sotillo, PhD. The research implicates MYC as a master regulator of chemosensitivity — making cancer cells more vulnerable to chemotherapy.
The study team increased levels of the Myc protein by inhibiting glycogen synthase kinase 3b (GSK-3b), an enzyme that normally marks Myc for degradation. The GSK-3 inhibitors elevated Myc levels and in doing so activated the death receptor pathway, enabling chemotherapy drugs to better kill Burkitt lymphoma cells.
One familiar GSK inhibitor is lithium chloride, an FDA-approved, inexpensive drug long established as a treatment for bipolar disorder. “If lithium can be repurposed as part of combination therapy for Burkitt lymphoma and other cancers, the path to a translational treatment could be short,” said Harrington, a graduate student in Penn’s Cell and Molecular Biology Graduate Group.
Before these results could become an approved therapy for patients with relapsed or refractory cancers, considerable work would need to occur, said Thomas-Tikhonenko, who added that the current study reinforces the importance of investigating cancer cell biology in the context of combination treatments.
In addition to his CHOP position, Thomas-Tikhonenko is on the faculty of the Perelman School of Medicine at the University of Pennsylvania.
Multiple grants, from the National Institutes of Health, the V Foundation for Cancer Research, the Institut National du Cancer and several European organizations, supported this research.
Colleen T. Harrington et al, “Transient stabilization, rather than inhibition, of MYC amplifies extrinsic apoptosis and therapeutic responses in refractory B-cell lymphoma,” Leukemia, published online March 26, 2019.