Targeting cholesterol pathways in p53 deficient head and neck cancers
Presenter: Jovanka Gencel-Augusto, BS;MS;PhD Session: Molecular Targets 1 Time: 4/20/2026 2:00:00 PM → 4/20/2026 5:00:00 PM
Authors
Jovanka Gencel-Augusto 1 , Nuo Tian 1 , Akshat Singhal 2 , Hua Li 3 , Liam Woerner 3 , Arthur Goldberg 1 , Daniel E. Johnson 4 , Jennifer Rubin Grandis 5 1 Otolaryngology - Head and Neck Surgery, UCSF - University of California San Francisco, San Francisco, CA, 2 UCSD Medical Ctr., San Diego, CA, 3 The University of California, San Francisco, San Francisco, CA, 4 Associate Professor, Dept. of Med. & Pharmacology, UCSF Helen Diller Family Comp. Cancer Center, San Francisco, CA, 5 UCSF - University of California San Francisco, San Francisco, CA
Abstract
Loss of p53 function is a major driver of poor outcomes in HNSCC, with over 70% of tumors harboring deactivating TP53 mutations. Despite decades of effort, mutant p53 remains “undruggable”. Cholesterol is essential for membrane integrity and oncogenic signaling, and elevated cholesterol levels correlate with aggressiveness across many cancers. In HNSCC, patients whose tumors express high levels of cholesterol-upregulating genes have a 50% higher risk of death, highlighting this pathway as a clinically relevant therapeutic target. We previously showed that HPV+ HNSCC cells retain wild-type (WT) p53 activity and that p53 transcriptionally regulates multiple metabolic pathways, including cholesterol-regulating genes. These observations led us to investigate how p53 loss rewires cholesterol metabolism and whether this metabolic shift creates a targetable vulnerability in p53-deficient HNSCC. Silencing WT p53 in HPV+ HNSCC cells (siRNA or CRISPRi) increased intracellular cholesterol and proliferation - an effect reversed by cholesterol deprivation. This p53 deficiency also elevated expression and maturation of SREBP1/2, master transcriptional regulators of cholesterol metabolism, along with multiple downstream SREBP targets. Elevated cholesterol and activated SREBP1/2 were similarly observed in HPV-negative p53-mutant HNSCC lines, indicating that p53-dependent cholesterol metabolism is a broader function independent of HPV status. In HNSCC patient-derived xenografts (PDXs), p53-mutant tumors exhibited higher expression and preferential nuclear localization of SREBP1 compared to p53-WT tumors, confirming cholesterol pathway reprogramming in vivo . To test pathway dependency, we examined the effects of SREBP1 genetic ablation (via siRNA or in CRISPR knock-out datasets) in HNSCC and other squamous carcinoma lines. SREBP1 loss selectively reduced viability in p53-deficient cells compared with WT counterparts. Pharmacologic inhibition of SREBP1/2 with the small molecule fatostatin also produced an average 2.7-fold greater cytotoxic response in p53-deficient versus p53-proficient HNSCC lines. In isogenic cell line-derived xenograft (CDX) models, fatostatin treatment (315 mg/kg over 32 days) significantly suppressed growth of p53-deficient tumors. A pan-cancer pharmacogenomic screen of >900 cell lines further identified p53 deficiency as a determinant of fatostatin sensitivity. Together, these findings demonstrate that p53 loss confers dependency on SREBP-driven cholesterol metabolism and support therapeutic targeting of this pathway in a genomically defined subset of HNSCC.
Disclosure
J. Gencel-Augusto, None.. N. Tian, None.. A. Goldberg, None.
Cited in
Control: 5395 · Presentation Id: 4680 · Meeting 21436