PHIP as a therapeutic target for driver-negative subtypes of melanoma, breast, and lung cancer

Abstract

The identification and targeting of key molecular drivers of melanoma and breast and lung cancer have substantially improved their therapy. However, subtypes of each of these three common, lethal solid tumors lack identified molecular drivers, and are thus not amenable to targeted therapies. Here we show that pleckstrin homology domain-interacting protein (PHIP) promotes the progression of these "driver-negative" tumors. Suppression of PHIP expression significantly inhibited both tumor cell proliferation and invasion, coordinately suppressing phosphorylated AKT, cyclin D1, and talin1 expression in all three tumor types. Furthermore, PHIP's targetable bromodomain is functional, as it specifically binds the histone modification H4K91ac. Analysis of TCGA profiling efforts revealed PHIP overexpression in triple-negative and basal-like breast cancer, as well as in the bronchioid subtype of nonsmall cell lung cancer. These results identify a role for PHIP in the progression of melanoma and breast and lung cancer subtypes lacking identified targeted therapies. The use of selective, anti-PHIP bromodomain inhibitors may thus yield a broad-based, molecularly targeted therapy against currently nontargetable tumors.

Advancements in the Development of non‐BET Bromodomain Chemical Probes

“…Pleckstrin homology domain interacting protein (PHIP) was originally identified through interactions with insulin receptor signaling proteins, yet has recently been reported as being involved in oncology . More specifically PHIP has been identified as a promoter of melanoma metastasis and as a potential therapeutic target for breast and lung cancer, emphasizing the need for further PHIP target validation . The second bromodomain of PHIP is atypical, with a Thr present within the binding site instead of the typical Asn which has made the development of PHIP(2) inhibitors more challenging.…”

“…[127] More specifically PHIP has been identified as ap romoter of melanoma metastasis and as ap otential therapeutic target for breast and lung cancer, emphasizing the need for further PHIP target validation. [128,129] The second bromodomain of PHIP is atypical,w ith aT hr present within the binding site insteado ft he typical Asn which has made the development of PHIP(2)i nhibitors more challenging. Recently, however,c ompounds 105-107 have emerged as fragment hits from as tudy using X-ray crystallography for fragment based drug discovery (Figure 17 a).…”

Control of mesenchymal stem cell biology by histone modifications

“…Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are both enzymes that regulate histone acetylation on lysine residues, but they produce opposite results [26,27]. In addition, proteins that contain specialized binding regions, such as bromodomains, are termed readers [28]; these proteins can recognize and bind to acetylated lysine residues, thus interacting with specific histone modifications [29].…”

PHIPing along: Evolution of PHIP as a cancer biomarker and a target for therapy

“…Recent studies have assigned novel roles to pleckstrin homology domain-interacting protein (PHIP) in tumor progression [ 1 , 2 ]. PHIP was initially shown to operate in the insulin-like growth factor receptor 1 (IGF1R)/PI3K signaling pathway in normal pancreatic islet cells [ 3 ].…”

“…In a separate recent study [ 2 ], we analyzed the role of PHIP in three cancers (breast and lung cancer, and melanoma) in which targeted therapies have shown the greatest efficacy. We focused on molecular subtypes of these cancers (termed “driver-negative”) lacking the known molecular drivers or targets for therapy, which are largely different in the three tumor types.…”