Co-targeting c-Met and DNA double-strand breaks (DSBs): Therapeutic strategies in BRCA-mutated gastric carcinomas

• Published in: Biochimie 2017-11, Vol.142, p.135-143
• Main Authors: Mihailidou, Chrysovalantou, Karamouzis, Michalis V., Schizas, Dimitrios, Papavassiliou, Athanasios G.
• Format: Article
• Language: English
• Subjects: Animals; BRCA proteins; c-MET; DNA Breaks, Double-Stranded - drug effects; Gastric cancer; Hepatocyte growth factor receptor; Humans; Molecular Targeted Therapy - methods; Mutation; Proto-Oncogene Proteins c-met - metabolism; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Tumor Suppressor Proteins - genetics
• ISSN: 0300-9084; 1638-6183
• DOI: 10.1016/j.biochi.2017.09.001

Gastric cancer (GC) is a threatening malignancy characterized by heterogeneity. Current therapies use DNA damaging agents, for example, chemotherapeutic agents and ionizing radiation (IR). However, a significant portion of GC patients develops therapeutic resistance to DNA damage response (DDR) - inducing agents. An important mechanism is the stimulation of the c-MET RTK, which is a tyrosine kinase receptor and its ligand hepatocyte growth factor (HGF), which facilitates cell survival by boosting DNA damage repair pathways and via escaping cell cycle arrest. A small subgroup of GC diagnosed patients has defects in BRCA1 and BRCA2 as mediators of DNA repair proteins. BRCA1/2 related-tumors acquire resistance to chemotherapy through the DSBs (DNA double strand breaks) repair pathways. However, BRCA2-deficient cells, are vulnerable to PARP [poly (ADP-ribose) polymerase] inhibitors as the replication forks collapse and the DNA-induced damage is not reversed. Herein, we pose that taking into consideration the defective DDR machinery can trigger GC cell sensitization to therapies via inhibition of DNA repair response. Inhibition of DNA damage response axis may designate cancer cells with BRCAness (BRCA-mutant cells) more vulnerable to DNA-damaging mediators, such as c-Met inhibitors. [Display omitted] •Gastric cancer patients develop resistance to DNA damage response-inducing agents.•MET oncogene-addicted gastric cancer cells are resistant to current treatment.•BRCAness (BRCA-mutant tumors) redirect to DNA double strand breaks repair pathways.•c-MET inhibitors are evaluated in gastric tumors to prevent acquired resistance.•Co-inhibition of c-Met/DNA repair is promising in gastric cancers with BRCAness.