title: Ras-MEK Signaling Mediates a Critical Chk1-Dependent DNA Damage Response in Cancer Cells.
abstract: Cancer cell line profiling to identify previously unrecognized kinase dependencies revealed a novel nonmutational dependency on the DNA damage response checkpoint kinase Chk1. Although Chk1 is a promising therapeutic target in p53-deficient cancers, we found that Ras-MEK signaling engages Chk1 in a subset of osteosarcoma, ovarian, and breast cancer cells to enable their survival upon DNA damage, irrespective of p53 mutation status. Mechanistically, Ras-MEK signaling drives Chk1 expression and promotes cancer cell growth that produces genotoxic stress that requires Chk1 to mediate a response to the consequent DNA damage. Reciprocally, Chk1 engages a negative feedback loop to prevent hyperactivation of Ras-MEK signaling, thereby limiting DNA damage. Furthermore, exogenous DNA damage promotes Chk1 dependency, and pharmacologic Chk1 inhibition combined with genotoxic chemotherapy potentiates a DNA damage response and tumor cell killing. These findings reveal a mechanism-based diagnostic strategy to identify cancer patients that may benefit from Chk1-targeted therapy.Mol Cancer Ther; 16(4); 694-704. ©2017 AACR.
authors.affiliation: Department of Discovery Oncology, Genentech, Inc., South San Francisco, California.
authors.forename: Ho-June
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, California.
authors.forename: Yi
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Protein Chemistry, Genentech, Inc., South San Francisco, California.
authors.forename: Victoria
authors.initials: V
authors.lastname: Pham
authors.affiliation: Department of Translational Oncology, Genentech, Inc., South San Francisco, California.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Blackwood
authors.affiliation: Department of Discovery Oncology, Genentech, Inc., South San Francisco, California.
authors.forename: Catherine
authors.initials: C
authors.lastname: Wilson
authors.affiliation: Department of Discovery Oncology, Genentech, Inc., South San Francisco, California.
authors.forename: Marie
authors.initials: M
authors.lastname: Evangelista
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, California.
authors.forename: Christiaan
authors.initials: C
authors.lastname: Klijn
authors.affiliation: Department of Discovery Oncology, Genentech, Inc., South San Francisco, California. settleman@calicolabs.com stokoe.david@gene.com.
authors.forename: David
authors.initials: D
authors.lastname: Stokoe
authors.affiliation: Department of Discovery Oncology, Genentech, Inc., South San Francisco, California. settleman@calicolabs.com stokoe.david@gene.com.
authors.forename: Jeff
authors.initials: J
authors.lastname: Settleman
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000071877:Checkpoint Kinase 1 / Q000235:genetics*; D004249:DNA Damage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D012516:Osteosarcoma / Q000188:drug therapy / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D010880:Piperidines / Q000008:administration & dosage / Q000627:therapeutic use; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D010880:Piperidines; D003841:Deoxycytidine; C000614032:GDC-0425; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D016283:Proto-Oncogene Proteins p21(ras); D000093542:Gemcitabine