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.

authors

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 M

doi

10.1073/pnas.1804779115

subject

Has Abstract

pub_date

2018-06-19 00:00:00

pages

E5766-E5775

issue

25

eissn

0027-8424

issn

1091-6490

pii

1804779115

journal_volume

115

pub_type

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