PHIP as a therapeutic target for driver-negative subtypes of melanoma, breast, and lung cancer.
Proc Natl Acad Sci U S A
; 115(25): E5766-E5775, 2018 06 19.
Article
in En
| MEDLINE
| ID: mdl-29866840
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Breast
/
Intracellular Signaling Peptides and Proteins
/
Triple Negative Breast Neoplasms
/
Pleckstrin Homology Domains
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Lung Neoplasms
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Melanoma
Limits:
Animals
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Female
/
Humans
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2018
Document type:
Article