Abstract 3031: PHIP is a therapeutic target for triple negative solid tumors
Authors: David De Semir, Vladimir Bezrookove, Mehdi Nosrati, Altaf A. Dar, Nathan Salomonis, Richard W. Sagebiel, Pierre Desprez, Robert J. Debs, Dirk Schadendorf, Mohammed Kashani-Sabet
Journal: Cancer Research (2017)

Abstract Targeted therapy relies on the classification of tumors according to the major molecular drivers of the malignant phenotype, which can then help decide the therapeutic treatment. However, a substantial subset of solid tumors does not express these markers, exemplified by the triple-negative subtype of breast cancer. Shared molecular factors that promote the progression of these tumors, and that represent a target for their therapy, are missing. We previously described a role for PHIP (Pleckstrin Homology domain-Interacting Protein) in the progression of melanoma, and demonstrated PHIP activation in triple-negative melanomas. Analysis of the TCGA profiling efforts in melanoma, breast and lung cancer revealed PHIP expression to be enriched in triple-negative breast cancer and in the bronchiad subtype of triple-negative lung cancer. Here we show the broad-based role of PHIP in the progression of triple-negative subtypes of three solid tumors (breast and lung cancer, and melanoma) defined by different mutational drivers and targeted therapies. By using a shRNA-based targeting of PHIP in in vitro and in vivo models, we have suppressed the malignant phenotype of triple-negative MDA-MB-231 and MDA-MB-436 human breast carcinoma cells. In addition, PHIP knockdown resulted in significant anti tumor effects in H1703 and Calu3 human lung cancer cells lacking mutations in EGFR, KRAS, and ALK, and in two short-term triple wild type melanoma cultures lacking mutations in BRAF, NRAS, and NF1. Suppression of PHIP expression resulted in inhibition of both tumor cell proliferation by cell survival and colony formation assays and invasion into matrigel in each of the tumor models examined, and was accompanied by suppression of pAKT, CCND1, TLN1, and ITGβ1 expression when assessed by western-blot or quantitative immunofluorescence. The PHIP protein contains two bromodomains that can be therapeutically targeted by small molecules. However, the functional activity of the PHIP bromodomains has been poorly characterized. We show that PHIP co-localizes with and binds to the acetylated histone modification H4K91ac, and that both are coordinately regulated upon growth factor stimulation suggesting a new function for PHIP as a chromatin remodeler. To conclude, our results identify a novel role for PHIP in the progression of solid tumors lacking the major molecular drivers, and suggest PHIP as a druggable target for the therapy of these malignancies. Citation Format: David De Semir, Vladimir Bezrookove, Mehdi Nosrati, Altaf A. Dar, Nathan Salomonis, Richard W. Sagebiel, Pierre Desprez, Robert J. Debs, Dirk Schadendorf, Mohammed Kashani-Sabet. PHIP is a therapeutic target for triple negative solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3031. doi:10.1158/1538-7445.AM2017-3031