Neutrophil extracellular traps (NETs), a web-like structure of cytosolic and granule
proteins assembled on decondensed
chromatin, kill pathogens and cause tissue damage in diseases. Whether NETs can kill
cancer cells is unexplored. Here, we report that a combination of
glutaminase inhibitor
CB-839 and
5-FU inhibited the growth of PIK3CA-mutant
colorectal cancers (
CRCs) in xenograft, syngeneic, and genetically engineered mouse models in part through NETs. Disruption of NETs by either
DNase I treatment or depletion of neutrophils in
CRCs attenuated the efficacy of the
drug combination. Moreover, NETs were present in
tumor biopsies from patients treated with the
drug combination in a phase II clinical trial. Increased NET levels in
tumors were associated with longer progression-free survival. Mechanistically, the
drug combination induced the expression of
IL-8 preferentially in PIK3CA-mutant
CRCs to attract neutrophils into the
tumors. Further, the
drug combination increased the levels of ROS in neutrophils, thereby inducing NETs.
Cathepsin G (CTSG), a
serine protease localized in NETs, entered CRC cells through the RAGE
cell surface protein. The internalized CTSG cleaved
14-3-3 proteins, released BAX, and triggered apoptosis in CRC cells. Thus, our studies illuminate a previously unrecognized mechanism by which
chemotherapy-induced NETs kill
cancer cells.