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PHIP as a therapeutic target for driver-negative subtypes of melanoma, breast, and lung cancer
David de Semir1, Vladimir Bezrookove1, Mehdi Nosrati1
1California Pacific Medical Center Research Institute, San Francisco, CA 94107.
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.
Insights
Pleckstrin homology domain-interacting protein (PHIP) drives progression in hard-to-treat melanoma, breast, and lung cancers lacking targeted therapies. Inhibiting PHIP shows promise for developing new treatments against these aggressive tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Targeted therapies have improved outcomes for melanoma, breast, and lung cancers.
- Certain aggressive subtypes of these cancers lack identified molecular drivers, limiting treatment options.
Purpose of the Study:
- To investigate the role of pleckstrin homology domain-interacting protein (PHIP) in
Main Methods:
- PHIP expression was suppressed in melanoma, breast, and lung cancer models.
- Tumor cell proliferation and invasion assays were performed.
- Expression of key proteins (pAKT, cyclin D1, talin1) and histone modification (H4K91ac) were analyzed.
- TCGA data was used to assess PHIP expression in patient tumor subtypes.
Main Results:
- PHIP suppression significantly inhibited proliferation and invasion in all three cancer types.
- PHIP inhibition reduced levels of phosphorylated AKT, cyclin D1, and talin1.
- PHIP's bromodomain was confirmed to bind H4K91ac.
- PHIP overexpression was observed in triple-negative/basal-like breast cancer and bronchioid non-small cell lung cancer.
Conclusions:
- PHIP is a key driver in melanoma, breast, and lung cancer subtypes that currently lack targeted therapies.
- Targeting PHIP, potentially with bromodomain inhibitors, offers a promising therapeutic strategy for these difficult-to-treat cancers.
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