Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors

Cancers of the brain and spine are the second most common kind of tumor in children, after cancers of the blood and bone marrow. Yet brain and spine tumors kill more children than any other cancer, in part because many become resistant to treatment. Like in other cancers, cells in brain and spine tumors often use a process called autophagy to survive the treatments that are used to try and kill them. This process allows cells to recycle proteins and other things inside the cell and use them for energy when the cell is under stress. In 2014, researchers reported that brain tumors carrying a mutation called BRAFV600E rely on autophagy to survive treatment with medications that target this mutation. These findings suggested that blocking autophagy might make the medications more effective against BRAFV600Emutant tumors and overcome the resistance. Now, Mulcahy Levy et al. – who include most of the researchers involved in the 2014 study – report that blocking autophagy does indeed overcome this kind of resistance in multiple types of tumor. The experiments made use of human brain tumor cells that can be grown in the laboratory and have been widely studied, as well as samples collected from patients. Mulcahy Levy et al. were able to block autophagy in the tumor cells by using genetic methods and, importantly, by using an approved and inexpensive drug that could be rapidly translated into clinical trials. Together these findings suggest that blocking autophagy in patients might be a safe and effective strategy to improve their response to existing therapies that target the BRAFV600E mutation. Future clinical trials are now needed to test more patients and verify if this treatment plan can be broadly effective in patients with these types of brain cancers.