Loss of CDKN2A remodels Golgi morphology to create a lipid peroxidation vulnerability

Loss of the tumor suppressor CDKN2A/p16 occurs in ~50% of human cancers, yet no therapies specifically target tumors with complete loss or reduced CDKN2A/p16 expression (hereafter CDKN2A/p16-Low). Identifying selective vulnerabilities in CDKN2A/p16-Low tumors therefore represents a critical unmet need. Here, we identify altered Golgi morphology as a vulnerability in CDKN2A/p16-Low melanoma. A CRISPR knockout screen revealed that genes associated with Golgi membranes are essential for CDKN2A/p16-Low cell survival. CDKN2A/p16 knockdown in human and murine cancer cells was associated with striking Golgi compaction. CDKN2A/p16 knockdown sensitized cells to pharmacologic Golgi disruption via lipid peroxidation both in vitro and in vivo. Notably, reduced Retinoblastoma-associated protein (RB1) expression did not recapitulate the increased sensitivity to Golgi disruption, supporting a role for non-canonical p16 functions in this vulnerability. Together, these findings uncover a previously unrecognized link between CDKN2A/p16-Low status and Golgi remodeling, revealing a Golgi-associated metabolic vulnerability in CDKN2A/p16-Low melanomas.