TY - JOUR TI - Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors AU - Mulcahy Levy, Jean M AU - Zahedi, Shadi AU - Griesinger, Andrea M AU - Morin, Andrew AU - Davies, Kurtis D AU - Aisner, Dara L AU - Kleinschmidt-DeMasters, BK AU - Fitzwalter, Brent E AU - Goodall, Megan L AU - Thorburn, Jacqueline AU - Amani, Vladimir AU - Donson, Andrew M AU - Birks, Diane K AU - Mirsky, David M AU - Hankinson, Todd C AU - Handler, Michael H AU - Green, Adam L AU - Vibhakar, Rajeev AU - Foreman, Nicholas K AU - Thorburn, Andrew A2 - Gilbertson, Richard J VL - 6 PY - 2017 DA - 2017/01/17 SP - e19671 C1 - eLife 2017;6:e19671 DO - 10.7554/eLife.19671 UR - https://doi.org/10.7554/eLife.19671 AB - Kinase inhibitors are effective cancer therapies, but tumors frequently develop resistance. Current strategies to circumvent resistance target the same or parallel pathways. We report here that targeting a completely different process, autophagy, can overcome multiple BRAF inhibitor resistance mechanisms in brain tumors. BRAFV600Emutations occur in many pediatric brain tumors. We previously reported that these tumors are autophagy-dependent and a patient was successfully treated with the autophagy inhibitor chloroquine after failure of the BRAFV600E inhibitor vemurafenib, suggesting autophagy inhibition overcame the kinase inhibitor resistance. We tested this hypothesis in vemurafenib-resistant brain tumors. Genetic and pharmacological autophagy inhibition overcame molecularly distinct resistance mechanisms, inhibited tumor cell growth, and increased cell death. Patients with resistance had favorable clinical responses when chloroquine was added to vemurafenib. This provides a fundamentally different strategy to circumvent multiple mechanisms of kinase inhibitor resistance that could be rapidly tested in clinical trials in patients with BRAFV600E brain tumors. KW - autophagy KW - BRAF V600E KW - brain tumor KW - chloroquine KW - pediatric JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -