title: Quantitative imaging for development of companion diagnostics to drugs targeting HGF/MET.
abstract: The limited clinical success of anti-HGF/MET drugs can be attributed to the lack of predictive biomarkers that adequately select patients for treatment. We demonstrate here that quantitative digital imaging of formalin fixed paraffin embedded tissues stained by immunohistochemistry can be used to measure signals from weakly staining antibodies and provides new opportunities to develop assays for detection of MET receptor activity. To establish a biomarker panel of MET activation, we employed seven antibodies measuring protein expression in the HGF/MET pathway in 20 cases and up to 80 cores from 18 human cancer types. The antibodies bind to epitopes in the extra (EC)- and intracellular (IC) domains of MET (MET4EC, SP44_METIC, D1C2_METIC), to MET-pY1234/pY1235, a marker of MET kinase activation, as well as to HGF, pSFK or pMAPK. Expression of HGF was determined in tumour cells (T_HGF) as well as in stroma surrounding cancer (St_HGF). Remarkably, MET4ECcorrelated more strongly with pMET (r= 0.47) than SP44_METIC(r= 0.21) or D1C2_METIC(r= 0.08) across 18 cancer types. In addition, correlation coefficients of pMET and T_HGF (r= 0.38) and pMET and pSFK (r= 0.56) were high. Prediction models of MET activation reveal cancer-type specific differences in performance of MET4EC, SP44_METICand anti-HGF antibodies. Thus, we conclude that assays to predict the response to HGF/MET inhibitors require a cancer-type specific antibody selection and should be developed in those cancer types in which they are employed clinically.
authors: Department of Biomedical Sciences Cedars-Sinai Medical Center Los Angeles California 90048 USA.
authors: Fangjin
authors: F
authors: Huang
authors: Department of Biomedical Sciences Cedars-Sinai Medical Center Los Angeles California 90048 USA.
authors: Zhaoxuan
authors: Z
authors: Ma
authors: Department of Biomedical Sciences Cedars-Sinai Medical Center Los Angeles California 90048 USA.
authors: Sara
authors: S
authors: Pollan
authors: Department of Biomedical Sciences Cedars-Sinai Medical Center Los Angeles California 90048 USA.
authors: Xiaopu
authors: X
authors: Yuan
authors: Department of Biomedical Sciences Cedars-Sinai Medical Center Los Angeles California 90048 USA.
authors: Steven
authors: S
authors: Swartwood
authors: Departments of Surgery Cedars-Sinai Medical Center Los Angeles California 90048 USA.
authors: Arkadiusz
authors: A
authors: Gertych
authors: Department of Biomedical Sciences Cedars-Sinai Medical Center Los Angeles California 90048 USA.
authors: Maria
authors: M
authors: Rodriguez
authors: Department of Pathology and Laboratory Medicine Cedars-Sinai Medical Center Los Angeles California 90048 USA.
authors: Jayati
authors: J
authors: Mallick
authors: Department of Pathology and Laboratory Medicine Cedars-Sinai Medical Center Los Angeles California 90048 USA.
authors: Sanica
authors: S
authors: Bhele
authors: Department of Pathology and Laboratory Medicine Cedars-Sinai Medical Center Los Angeles California 90048 USA.
authors: Maha
authors: M
authors: Guindi
authors: Department of Pathology and Laboratory Medicine Cedars-Sinai Medical Center Los Angeles California 90048 USA.
authors: Deepti
authors: D
authors: Dhall
authors: Department of Pathology and Laboratory Medicine Cedars-Sinai Medical Center Los Angeles California 90048 USA.
authors: Ann E
authors: AE
authors: Walts
authors: Department of Pathology and Laboratory Medicine Cedars-Sinai Medical Center Los Angeles California 90048 USA.
authors: Shikha
authors: S
authors: Bose
authors: Department of Pathology and Laboratory Medicine Cedars-Sinai Medical Center Los Angeles California 90048 USA.
authors: Mariza
authors: M
authors: de Peralta Venturina
authors: Department of Pathology and Laboratory Medicine Cedars-Sinai Medical Center Los Angeles California 90048 USA.
authors: Alberto M
authors: AM
authors: Marchevsky
authors: Department of Pathology and Laboratory Medicine Cedars-Sinai Medical Center Los Angeles California 90048 USA.
authors: Daniel J
authors: DJ
authors: Luthringer
authors: Institute of Molecular Medicine, Martin-Luther-University 06120 Halle Germany.
authors: Stephan M
authors: SM
authors: Feller
authors: Department of Biomedical Sciences Cedars-Sinai Medical Center Los Angeles California 90048 USA.
authors: Benjamin
authors: B
authors: Berman
authors: Department of Biomedical SciencesCedars-Sinai Medical CenterLos AngelesCalifornia90048USA; Departments of SurgeryCedars-Sinai Medical CenterLos AngelesCalifornia90048USA; Cancer Biology Program, Departments of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical CenterLos AngelesCalifornia90048USA.
authors: Michael R
authors: MR
authors: Freeman
authors: Data Management Services, Inc., National Cancer Institute at Frederick Frederick Maryland 21702 USA.
authors: W Gregory
authors: WG
authors: Alvord
authors: Laboratory of Molecular Oncology Center for Cancer and Cell Biology, Van Andel Research Institute Grand Rapids Michigan 49503 USA.
authors: George
authors: G
authors: Vande Woude
authors: Department of Pathology and Laboratory Medicine Cedars-Sinai Medical Center Los Angeles California 90048 USA.
authors: Mahul B
authors: MB
authors: Amin
authors: Department of Biomedical SciencesCedars-Sinai Medical CenterLos AngelesCalifornia90048USA; Department of Pathology and Laboratory MedicineCedars-Sinai Medical CenterLos AngelesCalifornia90048USA.
authors: Beatrice S
authors: BS
authors: Knudsen
keywords: HGF/MET; multi‐cancer tissue microarray; quantitative imaging