PIKFYVE inhibitors trigger interleukin‐24‐dependent cell death of autophagy‐dependent melanoma

Inhibitors specifically targeting the 1‐phosphatidylinositol 3‐phosphate 5‐kinase (PIKFYVE) disrupt lysosome homeostasis, thereby selectively terminating autophagy‐dependent human cancer cells in vivo as well as in vitro without harming the viability of nonmalignant cells. To elucidate the mechanism by which PIKFYVE inhibition induces cell death, autophagy‐dependent melanoma cells were compared with normal foreskin fibroblasts. RNA sequence profiling suggested that PIKFYVE inhibitors upregulated an endoplasmic reticulum (ER) stress response involving interleukin‐24 (IL24; also known as MDA7) selectively in melanoma cells. Subsequent biochemical and genetic analyses confirmed these results and extended them to tumor xenografts in which tumor formation and expansion were inhibited. IL24 expression was upregulated by the DDIT3/CHOP/CEBPz transcription factor, a component of the PERK‐dependent ER‐stress response. Ectopic expression of IL24‐induced cell death in melanoma cells, but not in foreskin fibroblasts, whereas ablation of the IL24 gene in melanoma cells prevented death. IL24 upregulation was triggered specifically by PIKFYVE inhibition. Thus, unlike thapsigargin and tunicamycin, which induce ER‐stress indiscriminately, PIKFYVE inhibitors selectively terminated PIKFYVE‐sensitive melanoma by inducing IL24‐dependent ER‐stress. Moreover, induction of cell death by a PIKFYVE inhibitor together with ectopic expression of IL24 protein was cumulative, thereby confirming the therapeutic potential of PIKFYVE inhibitors in the treatment of melanoma. PIKFYVE inhibitors selectively kill melanoma cells by disrupting lysosome homeostasis, which triggers an ER‐stress response that upregulates expression of glycosylated interleukin‐24 (IL24). IL24 amplifies the ER‐stress response to induce cell death. Thapsigargin and tunicamycin also trigger ER‐stress, but they are toxic to normal cells as well as cancer cells.