title: KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer.
abstract: Investigating therapeutic "outliers" that show exceptional responses to anti-cancer treatment can uncover biomarkers of drug sensitivity. We performed preclinical trials investigating primary murine acute myeloid leukemias (AMLs) generated by retroviral insertional mutagenesis in KrasG12D"knockin" mice with the MEK inhibitor PD0325901 (PD901). One outlier AML responded and exhibited intrinsic drug resistance at relapse. Loss of wild-type (WT) Kras enhanced the fitness of the dominant clone and rendered it sensitive to MEK inhibition. Similarly, human colorectal cancer cell lines with increased KRAS mutant allele frequency were more sensitive to MAP kinase inhibition, and CRISPR-Cas9-mediated replacement of WT KRAS with a mutant allele sensitized heterozygous mutant HCT116 cells to treatment. In a prospectively characterized cohort of patients with advanced cancer, 642 of 1,168 (55%) with KRAS mutations exhibited allelic imbalance. These studies demonstrate that serial genetic changes at the Kras/KRAS locus are frequent in cancer and modulate competitive fitness and MEK dependency.
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Burgess
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Hwang
authors.affiliation: Department of Discovery Oncology, Genentech, South San Francisco, CA 94080, USA.
authors.forename: Rana
authors.initials: R
authors.lastname: Mroue
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Bielski
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Anica M
authors.initials: AM
authors.lastname: Wandler
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Huang
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Ari J
authors.initials: AJ
authors.lastname: Firestone
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, CA 94080, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Young
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, CA 94080, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Lacap
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, CA 94080, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Crocker
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Asthana
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Davis
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Keiko
authors.initials: K
authors.lastname: Akagi
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Molecular Biology, Genentech, South San Francisco, CA 94080, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haley
authors.affiliation: Department of Discovery Oncology, Genentech, South San Francisco, CA 94080, USA.
authors.forename: David
authors.initials: D
authors.lastname: Stokoe
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, CA 94080, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
authors.affiliation: Department of Discovery Oncology, Genentech, South San Francisco, CA 94080, USA. Electronic address: evangelista.marie@gene.com.
authors.forename: Marie
authors.initials: M
authors.lastname: Evangelista
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA. Electronic address: kevin.shannon@ucsf.edu.
authors.forename: Kevin
authors.initials: K
authors.lastname: Shannon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D060965:Clonal Evolution; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012190:Retroviridae
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C117307:KRAS protein, human; C506614:mirdametinib; D004159:Diphenylamine; D016283:Proto-Oncogene Proteins p21(ras)
keywords: AML; KRAS; MEK inhibition; allelic imbalance; colorectal cancer; drug resistance