The combination of the glycolysis inhibitor 2-DG and sorafenib can be effective against sorafenib-tolerant persister cancer cells

Chemotherapy remains a major clinical option for the successful treatment of cancer by eliminating fast-growing populations of cancer cells. However, drug resistance causes the failure of antitumor treatment. Increasing evidence suggests that a small subpopulation of cancer cells will enter a "persister state" under drug pressure. The persister cell pool constitutes a reservoir from which drug resistance may emerge. Therefore, targeting persister cells presents a therapeutic opportunity to prevent drug resistance and impede tumor relapse. Materials and

These findings suggest that such a combination can effectively hamper persister cell growth and may represent a promising therapeutic strategy to prevent persister cell resistance.

RT-qPCR, Western blot, Seahorse, apoptosis assay, clonogenic assay, and xenografted mouse model were used for this study.

We showed that a similar therapy-resistant cell state underlies the behavior of persister cells derived from sorafenib treatments with reversible, nonmutational mechanisms. Then, we demonstrated that persister cells showed upregulated glycolysis, as evidenced by higher ECAR, as well as increased glucose consumption and lactate production. A database analysis showed that sorafenib-tolerant persister cells exhibited the increased expression of the glycolytic enzyme hexokinase 2, which is closely related to the poor prognosis in liver cancer. We found that the combined treatment with the glycolytic inhibitor 2-DG and sorafenib increased persister cell apoptosis and inhibited colony formation. Consequently, we demonstrated that when persister cells were exposed to a low concentration of sorafenib, they suffered mitochondrial dysfunction but showed compensatory increases in glycolysis, which contributes to cell growth and proliferation. Finally, we showed that the combination of 2-DG and sorafenib reduced persister tumor growth in mice. Conclusions: These findings suggest that such a combination can effectively hamper persister cell growth and may represent a promising therapeutic strategy to prevent persister cell resistance.