Inhibition of c-MET increases the antitumour activity of PARP inhibitors in gastric cancer models.

Journal of Cellular and Molecular Medicine
Evangelos KoustasAthanasios G Papavassiliou

Abstract

Gastric cancer is the fifth most common malignancy and the third leading cause of cancer-related death worldwide. Activation of c-MET increases tumour cell survival through the initiation of the DNA damage repair pathway. PARP is an essential key in the DNA damage repair pathway. The primary role of PARP is to detect and initiate an immediate cellular response to single-strand DNA breaks. Tumours suppressor genes such as BRCA1/2 are closely associated with the DNA repair pathway. In BRCA1/2 mutations or deficiency status, cells are more likely to develop additional genetic alterations and chromosomal instability and can lead to cancer. In this study, we investigate the role of c-MET and PARP inhibition in a gastric cancer model. We exploited functional in vitro and in vivo experiments to assess the antitumour potential of co-inhibition of c-MET (SU11274) and PARP (NU1025). This leads to a reduction of gastric cancer cells viability, especially after knockdown of BRCA1/2 through apoptosis and induction of γ-Η2ΑΧ. Moreover, in AGS xenograft models, the combinatorial treatment of NU1025 plus SU11274 reduced tumour growth and triggers apoptosis. Collectively, our data may represent a new therapeutic approach for GC thought co-inhib...Continue Reading

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Citations

Jan 27, 2021·Critical Reviews in Oncology/hematology·Fatemeh MoosaviOmidreza Firuzi
Jun 26, 2021·Journal of Experimental & Clinical Cancer Research : CR·Yali WangYanmei Zou

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Methods Mentioned

BETA
xenograft
xenografts

Clinical Trials Mentioned

NCT01063517
NCT01924533

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