American Association for Cancer Research
21598290cd140049-sup-supp_legemds.pdf (186.29 kB)

Supplementary Figure Legends from Autophagy Inhibition Improves Chemosensitivity in BRAFV600E Brain Tumors

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journal contribution
posted on 2023-04-03, 20:49 authored by Jean M. Mulcahy Levy, Joshua C. Thompson, Andrea M. Griesinger, Vladimir Amani, Andrew M. Donson, Diane K. Birks, Michael J. Morgan, David M. Mirsky, Michael H. Handler, Nicholas K. Foreman, Andrew Thorburn

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Autophagy inhibition is a potential therapeutic strategy in cancer, but it is unknown which tumors will benefit. The BRAFV600E mutation has been identified as important in pediatric central nervous system (CNS) tumors and is known to affect autophagy in other tumor types. We evaluated CNS tumor cells with BRAFV600E and found that mutant (but not wild-type) cells display high rates of induced autophagy, are sensitive to pharmacologic and genetic autophagy inhibition, and display synergy when the clinically used autophagy inhibitor chloroquine was combined with the RAF inhibitor vemurafenib or standard chemotherapeutics. Importantly, we also demonstrate that chloroquine can improve vemurafenib sensitivity in a resistant ex vivo primary culture and provide the first demonstration in a patient harboring the V600E mutation treated with vemurafenib that the addition of chloroquine can improve clinical outcomes. These findings suggest that CNS tumors with BRAFV600E are autophagy-dependent and should be targeted with autophagy inhibition in combination with other therapeutic strategies.Significance: Autophagy inhibition may improve cancer therapy, but it is unclear which tumors will benefit. We found that BRAF mutations cause brain tumor cells to depend on autophagy and display selective chemosensitization with autophagy inhibition. We present a pediatric case in which deliberate autophagy inhibition halted tumor growth and overcame acquired BRAF-inhibition resistance. Cancer Discov; 4(7); 773–80. ©2014 AACR.This article is highlighted in the In This Issue feature, p. 745

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