Investigators at the University of Colorado are now reporting that adding the anti-malaria drug chloroquine to standard therapies may help combat resistance to therapy and also resensitize patients with glioblastoma to targeted treatments that had previously stopped working. Investigators looked at vemurafenib-resistant brain tumors and found that chloroquine was highly effective.1
It is well known that kinase inhibitors are effective cancer therapies. However, the tumors frequently develop resistance. Most of the current strategies to circumvent resistance are designed to target the same pathways or parallel pathways. Now, researchers report that targeting a completely different process, autophagy, may help overcome multiple BRAF inhibitor resistance mechanisms in patients with glioblastoma.
In a small number of patients with brain tumors, the team found that adding the autophagy inhibitor chloroquine after failure of the BRAFV600E inhibitor vemurafenib, it is possible to overcome kinase inhibitor resistance. The investigators have demonstrated that genetic and pharmacological autophagy inhibition can overcome molecularly distinct resistance mechanisms.
The addition of autophagy inhibition to targeted treatments may have benefits beyond glioblastoma and beyond only BRAF-positive cancers. Since chloroquine has already earned approval from the U.S. Food and Drug Administration as a safe and effective (and inexpensive) treatment for malaria, the paper points out that it should be possible to quickly test the effectiveness of adding autophagy inhibition to a larger sample of BRAF-positive glioblastoma and patients with other brain tumors. It is hoped that this approach also may be applicable to other common mutations and disease sites.
1. Mulcahy Levy JM, Zahedi S, Griesinger AM, et al. Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors. Elife. 2017 Jan 17;6. doi: 10.7554/eLife.19671