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.
journal_name
Proc Natl Acad Sci U S Aauthors
de Semir D,Bezrookove V,Nosrati M,Dar AA,Wu C,Shen J,Rieken C,Venkatasubramanian M,Miller JR 3rd,Desprez PY,McAllister S,Soroceanu L,Debs RJ,Salomonis N,Schadendorf D,Cleaver JE,Kashani-Sabet Mdoi
10.1073/pnas.1804779115subject
Has Abstractpub_date
2018-06-19 00:00:00pages
E5766-E5775issue
25eissn
0027-8424issn
1091-6490pii
1804779115journal_volume
115pub_type
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