Abstract LB093: PHIP suppresses NuRD to enable the growth of SWI/SNF-mutant cancers

Abstract SWI/SNF chromatin remodeling complexes are perturbed in 20% of all cancers and in several developmental disorders, yet the mechanisms by which these mutations dysregulate transcription and drive disease are poorly understood. To both elucidate these mechanisms and identify vulnerabilities caused by these mutations, we leveraged genome-wide CRISPR-Cas9 screening in hundreds of cancer cell lines and identified the chromatin reader protein PHIP as a specific dependency in cancers with broadly disrupted SWI/SNF function. Mechanistically, we reveal that PHIP cooperates with SWI/SNF to facilitate transcriptional activation by ubiquitinating and suppressing subunits of the repressive Nucleosome Remodeling and Deacetylase (NuRD) complex. We demonstrate that loss of SWI/SNF results in NuRD complexes accumulating at promoters where they would otherwise cause widespread transcriptional silencing if not antagonized by PHIP. Collectively, we identify PHIP as a regulator of the interplay between distinct chromatin regulators that function in development and disease and as a targetable vulnerability in cancers with broad SWI/SNF inactivation. Citation Format: Hayden A. Malone, Jacqueline A. Myers, Emma G. Gruss, Marc A. Morgan, Jake D. Friske, Tabitha C. McCarty, John J. Navarro, Sarah Robinson, Rebecca L. Halliburton, Sandra J. Kietlinska, Francisca N. De Luna Vitorino, Baranda S. Hansen, Shondra M. Pruett-Miller, Benjamin A. Garcia, Martine F. Roussel, Janet F. Partridge, Charles W. Roberts. PHIP suppresses NuRD to enable the growth of SWI/SNF-mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB093.