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

Abstract

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.

Keywords: BRCA proteins; Gastric cancer; HR; Hepatocyte growth factor receptor; c-MET.