title: Molecular pathways: targeting the dependence of mutant RAS cancers on the DNA damage response.
abstract: Of the genes mutated in cancer, RAS remains the most elusive to target. Recent technological advances and discoveries have greatly expanded our knowledge of the biology of oncogenic Ras and its role in cancer. As such, it has become apparent that a property that intimately accompanies RAS-driven tumorigenesis is the dependence of RAS-mutant cells on a number of nononcogenic signaling pathways. These dependencies arise as a means of adaptation to Ras-driven intracellular stresses and represent unique vulnerabilities of mutant RAS cancers. A number of studies have highlighted the dependence of mutant RAS cancers on the DNA damage response and identified the molecular pathways that mediate this process, including signaling from wild-type Ras isoforms, ATR/Chk1, and DNA damage repair pathways. Here, we review these findings, and we discuss the combinatorial use of DNA-damaging chemotherapy with blockade of wild-type H- and N-Ras signaling by farnesyltransferase inhibitors, Chk1 inhibitors, or small-molecule targeting DNA damage repair as potential strategies through which the dependence of RAS cancers on the DNA damage response can be harnessed for therapeutic intervention.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York. Elda.Grabocka@nyumc.org.
authors.forename: Elda
authors.initials: E
authors.lastname: Grabocka
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York.
authors.forename: Cosimo
authors.initials: C
authors.lastname: Commisso
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York.
authors.forename: Dafna
authors.initials: D
authors.lastname: Bar-Sagi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D051231:Farnesyltranstransferase; D011494:Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D016283:Proto-Oncogene Proteins p21(ras)