Targeting Autophagy in BRAF-Mutant Tumors

摘要

Summary: Recent studies have highlighted the opportunity to treat cancer by inhibiting autophagy, but have also raised important caveats with this idea. An article in this issue of Cancer Discovery adds to accumulating evidence suggesting that we should focus our efforts (at least initially) on specific tumors where we are most likely to see beneficial effects. Macroautophagy (which we refer to as autophagy) is the process by which cellular material is delivered to lysosomes via vesicles called autophagosomes. Autophagy is widely viewed as being important in cancer and, in the last year, several clinical trials reported deliberate attempts to inhibit autophagy along with various other anticancer drugs in multiple tumor types. The key word in the previous sentence is "deliberate"—we also know that many anticancer agents inadvertently alter autophagy (in some cases stimulating and in others inhibiting the process). This means that even during standard therapy, autophagy is likely being manipulated in patients with cancer whether we want to do so or not. Is such autophagy manipulation a good thing or a bad thing to be doing? The big issue is that autophagy has multiple, often competing, effects on tumor cell behavior (1), and autophagy inhibition could therefore sometimes be good and sometimes bad from the perspective of a patient with cancer (2). This creates a conundrum: How should we try to manipulate autophagy in cancer patients, and should we be doing the same in everyone? An article in this issue of Cancer Discovery from the laboratories of Janice Mehnert and Eileen White (3) adds to accumulating evidence that BRAF-mutant tumors are good candidates for deliberate autophagy inhibition. The authors use a genetically engineered mouse model (GEMM) of Braf-mutant, Pten-null melanoma to show that autophagy inhibition causes tumor growth inhibition, leading to extended survival of the mice. This work follows several studies concluding that autophagy inhibition can have antitumor effects especially on tumors driven by RAS pathway mutations. For example, an elegant article also from Dr. White's group showed a profound antitumor effect on Kras-driven murine lung tumors when autophagy was acutely inhibited by whole-body knockout of the Atg7 gene (4).