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The positive results of the apatinib phase III trial have cast new light on treatment for patients with advanced gastric cancer (GC). However, in terms of safety, apatinib toxicities may lead to a dose modification or treatment interruption. Therefore, proper intervention is urgently needed to help patients benefit from apatinib treatment. In this study, we found that apatinib promoted autophagy activation via upregulation of ATG7 expression and autophagy inhibition enhanced apatinib-induced apoptosis. With microRNA and circular RNA-sequencing analyses of GC xenograft models, we demonstrated that  circRACGAP1  functioned as an endogenous sponge for  miR-3657  to inhibit its activity and further upregulate  ATG7  expression. Silencing of  circRACGAP1  inhibited apatinib-induced autophagy, which was rescued by  miR-3657 . Moreover, knockdown of  circRACGAP1  sensitized GC cells to apatinib via autophagy inhibition in vitro and in vivo. These findings provided the first evidence that the  circRACGAP1 - miR-3657-ATG7  axis mediates a novel regulatory pathway critical for the regulation of apatinib sensitivity in GC. Thus, specific blockage of  circRACGAP1  may be a potential therapeutic strategy to reduce the toxicities of apatinib and enhance its therapeutic effect in human GC.

Silencing of circRACGAP1 sensitizes gastric cancer cells to apatinib via modulating autophagy by targeting miR-3657 and ATG7