Τίτλος:
Co-targeting c-Met and DNA double-strand breaks (DSBs): Therapeutic strategies in BRCA-mutated gastric carcinomas
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM)
Συγγραφείς:
Mihailidou, C.
Karamouzis, M.V.
Schizas, D.
Papavassiliou, A.G.
Λέξεις-κλειδιά:
BRCA protein; BRCA1 protein; BRCA2 protein; protein; scatter factor receptor; unclassified drug; scatter factor receptor; tumor suppressor protein, cancer cell; cancer patient; DNA damage response; DNA repair; double stranded DNA break; human; phase 1 clinical trial (topic); phase 2 clinical trial (topic); phase 3 clinical trial (topic); protein function; protein structure; protein targeting; randomized controlled trial (topic); Review; signal transduction; stomach carcinoma; animal; double stranded DNA break; drug effect; genetics; metabolism; molecularly targeted therapy; mutation; procedures; stomach tumor, Animals; DNA Breaks, Double-Stranded; Humans; Molecular Targeted Therapy; Mutation; Proto-Oncogene Proteins c-met; Stomach Neoplasms; Tumor Suppressor Proteins
DOI:
10.1016/j.biochi.2017.09.001
