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

Amalric, A.; Yang, B.; Scarpati, R.; Uboveja, A.; Zheng, R.; Tom, A.; Cole, A. R.; Huacachino, A. A.; Liu, Q.; Snyder, N. W.; Kossenkov, A. V.; Aird, K. M.; Buj, R.

doi:10.64898/2026.11.10.765755

bioRxiv · 10.64898/2026.11.10.765755

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

Amalric, A.·Yang, B.·Scarpati, R.·Uboveja, A.·Zheng, R.·Tom, A.·Cole, A. R.·Huacachino, A. A.·Liu, Q.·Snyder, N. W.·Kossenkov, A. V.·Aird, K. M.·Buj, R.

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Abstract

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.

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Amalric, A., Yang, B., Scarpati, R., Uboveja, A., Zheng, R., Tom, A., Cole, A. R., Huacachino, A. A., Liu, Q., Snyder, N. W., Kossenkov, A. V., Aird, K. M., Buj, R.. 2026-11-12. Loss of CDKN2A remodels Golgi morphology to create a lipid peroxidation vulnerability. https://doi.org/10.64898/2026.11.10.765755

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