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C-MET as a potential therapeutic target and biomarker in cancer.

ABSTRACT: The receptor tyrosine kinase c-MET and its ligand, hepatocyte growth factor (HGF), regulate multiple cellular processes that stimulate cell proliferation, invasion and angiogenesis. This review provides an overview of the evidence to support c-MET or the HGF/c-MET signaling pathway as relevant targets for personalized cancer treatment based on high frequencies of c-MET and/or HGF overexpression, activation, amplification in non-small cell lung carcinoma (NSCLC), gastric, ovarian, pancreatic, thyroid, breast, head and neck, colon and kidney carcinomas. Additionally, the current knowledge of small molecule inhibitors (tivantinib [ARQ 197]), c-MET/HGF antibodies (rilotumumab and MetMAb) and mechanisms of resistance to c-MET-targeted therapies are discussed.

SUBMITTER: Sierra JR

PROVIDER: S-EPMC3225018 | biostudies-other | 2011 Nov

REPOSITORIES: biostudies-other

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c-MET as a potential therapeutic target and biomarker in cancer.

Sierra J Rafael JR Tsao Ming-Sound MS

Therapeutic advances in medical oncology 20111101 1 Suppl

The receptor tyrosine kinase c-MET and its ligand, hepatocyte growth factor (HGF), regulate multiple cellular processes that stimulate cell proliferation, invasion and angiogenesis. This review provides an overview of the evidence to support c-MET or the HGF/c-MET signaling pathway as relevant targets for personalized cancer treatment based on high frequencies of c-MET and/or HGF overexpression, activation, amplification in non-small cell lung carcinoma (NSCLC), gastric, ovarian, pancreatic, thy ...[more]

PMID: 22128285

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Project description:BackgroundWe have recently reported that the expression of peptidylarginine deiminase 2 (PADI2) is regulated by EGF in mammary cancer cells and appears to play a role in the proliferation of normal mammary epithelium; however, the role of PADI2 in the pathogenesis of human breast cancer has yet to be investigated. Thus, the goals of this study were to examine whether PADI2 plays a role in mammary tumor progression, and whether the inhibition of PADI activity has anti-tumor effects.MethodsRNA-seq data from a collection of 57 breast cancer cell lines was queried for PADI2 levels, and correlations with known subtype and HER2/ERBB2 status were evaluated. To examine PADI2 expression levels during breast cancer progression, the cell lines from the MCF10AT model were used. The efficacy of the PADI inhibitor, Cl-amidine, was tested in vitro using MCF10DCIS cells grown in 2D-monolayers and 3D-spheroids, and in vivo using MCF10DCIS tumor xenografts. Treated MCF10DCIS cells were examined by flow-cytometry to determine the extent of apoptosis and by RT2 Profiler PCR Cell Cycle Array to detect alterations in cell cycle associated genes.ResultsWe show by RNA-seq that PADI2 mRNA expression is highly correlated with HER2/ERBB2 (p = 2.2 × 106) in luminal breast cancer cell lines. Using the MCF10AT model of breast cancer progression, we then demonstrate that PADI2 expression increases during the transition of normal mammary epithelium to fully malignant breast carcinomas, with a strong peak of PADI2 expression and activity being observed in the MCF10DCIS cell line, which models human comedo-DCIS lesions. Next, we show that a PADI inhibitor, Cl-amidine, strongly suppresses the growth of MCF10DCIS monolayers and tumor spheroids in culture. We then carried out preclinical studies in nude (nu/nu) mice and found that Cl-amidine also suppressed the growth of xenografted MCF10DCIS tumors by more than 3-fold. Lastly, we performed cell cycle array analysis of Cl-amidine treated and control MCF10DCIS cells, and found that the PADI inhibitor strongly affects the expression of several cell cycle genes implicated in tumor progression, including p21, GADD45α, and Ki67.ConclusionTogether, these results suggest that PADI2 may function as an important new biomarker for HER2/ERBB2+ tumors and that Cl-amidine represents a new candidate for breast cancer therapy.

Project description:BackgroundGlobally, lung cancer causes the most cancer death. While molecular therapy progress, including epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), has provided remarkable therapeutic effects, some patients remain resistant to these therapies and therefore new target development is required. Cytoskeleton-associated membrane protein 4 (CKAP4) is a receptor of the secretory protein Dickkopf-1 (DKK1) and the binding of DKK1 to CKAP4 promotes tumor growth via Ak strain transforming (AKT) activation. We investigated if CKAP4 functions as a diagnostic biomarker and molecular therapeutic target for lung cancer.MethodsCKAP4 secretion with exosomes from lung cancer cells and the effect of CKAP4 palmitoylation on its trafficking to the exosomes were examined. Serum CKAP4 levels were measured in mouse xenograft models, and 92 lung cancer patients and age- and sex-matched healthy controls (HCs). The lung cancer tissues were immunohistochemically stained for DKK1 and CKAP4, and their correlation with prognosis and serum CKAP4 levels were investigated. Roles of CKAP4 in the lung cancer cell proliferation were examined, and the effects of the combination of an anti-CKAP4 antibody and osimertinib, a third generation TKI, on anti-tumor activity were tested using in vitro and in vivo experiments.ResultsCKAP4 was released from lung cancer cells with exosomes, and its trafficking to exosomes was regulated by palmitoylation. CKAP4 was detected in sera from mice inoculated with lung cancer cells overexpressing CKAP4. In 92 lung cancer patients, positive DKK1 and CKAP4 expression patients showed worse prognoses. Serum CKAP4 positivity was higher in lung cancer patients than in HCs. After surgical operation, serum CKAP4 levels were decreased. CKAP4 overexpression in lung cancer cells promoted in vitro cell proliferation and in vivo subcutaneous tumor growth, which were inhibited by an anti-CKAP4 antibody. Moreover, treatment with this antibody or osimertinib, a third generation TKI, inhibited AKT activity, sphere formation, and xenograft tumor growth in lung cancer cells harboring EGFR mutations and expressing both DKK1 and CKAP4, while their combination showed stronger inhibition.ConclusionsCKAP4 may represent a novel biomarker and molecular target for lung cancer, and combination therapy with an anti-CKAP4 antibody and osimertinib could provide a new lung cancer therapeutic strategy.

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C-MET as a potential therapeutic target and biomarker in cancer.

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c-MET as a potential therapeutic target and biomarker in cancer.

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