TB-19AUTOPHAGY INHIBITION OVERCOMES RESISTANCE TO BRAF INHIBITION IN BRAIN TUMORS

Abstract

TB-19. AUTOPHAGY INHIBITION OVERCOMES RESISTANCE TO BRAF INHIBITION IN BRAIN TUMORS Jean Mulcahy Levy, Shadi Zahedi, Andrea Griesinger, Kurtis Davies, Dara Eisner, B.K. Kleinschmidt-DeMasters, Brent Fitzwalter, Megan Goodall, Vladimir Amani, Andrew Donson, Diane Birks, David Mirsky, Todd Hankinson, Michael Handler, Nicholas Foreman, and Andrew Foreman; Department of Pediatrics, University of Colorado Denver, Aurora, CO, USA Kinase inhibitors are effective in cancer treatment but beneficial effects are almost invariably short-lived as tumors become resistant to the inhibitor. Current strategies to circumvent resistance target the same pathway another way or inhibiting a parallel pathway. Here, we report that it is possible to overcome resistance to the BRAF inhibitor vemurafenib in BRAF mutant brain tumors by targeting a completely different cellular process. BRAF mutation occurs in a high proportion of children’s brain tumors and we previously reported that these brain tumor cells are autophagydependent. We also reported a patient who was successfully treated after failure of vemurafenib by adding the autophagy inhibitor chloroquine (CQ) to vemurafenib suggesting that autophagy inhibition overcame kinase inhibitor resistance. In the present study, we tested this hypothesis by modeling acquisition of vemurafenib resistance in brain tumor cell lines. Both genetic and pharmacological inhibition of autophagy could overcome resistance due to multiple mutations and compensatory mechanisms. To evaluate clinically-acquired drug resistance, we tested tumor slices and primary tumor cells from patients with resistance to vemurafenib. Pharmacological inhibition of autophagy reversed resistance, inhibited tumor cell growth, and increased tumor cell death in vitro; moreover, when it was possible to test, the same patient had favorable clinical responses when CQ was added to vemurafenib. Our results provide proof of concept for a fundamentally different way to circumvent kinase inhibitor resistance in cancer therapy, and suggest a strategy for improved treatment of a large proportion of children’s brain tumors that could be rapidly tested in clinical trials. Neuro-Oncology 18:iii169–iii173, 2016. doi:10.1093/neuonc/now084.13 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.