The epithelial polarity regulator galectin-9 induces fatal frustrated autophagy in KRAS mutant colon carcinoma that depends on elevated basal autophagic flux.

Oncogenic mutation of KRAS in colorectal cancer (CRC) confers resistance to both chemotherapy and EGFR-targeted therapy. We uncovered that KRAS mutant (KRASmut) CRC is uniquely sensitive to treatment with recombinant Galectin-9 (rGal-9), a recently established regulator of epithelial polarity. Upon treatment of CRC cells, rGal-9 rapidly internalizes via clathrin- and PKC/CRAF/MEK-dependent endocytosis and accumulates in the lysosomal compartment. Treatment with rGal-9 is accompanied by activation of frustrated autophagy in KRASmut CRC, but not in BRAFmut CRC. In KRASmut CRC, rGal-9 acts as a lysosomal inhibitor that inhibits autophagosome/lysosome fusion, leading to autophagosome accumulation, excessive lysosomal swelling and cell death. This antitumor activity of rGal-9 directly correlates with elevated basal autophagic flux in KRASmut cancer cells. Thus, rGal-9 has potent antitumor activity towards refractory KRASmut CRC cells that may be exploitable for therapeutic use.