title: Radiation Resistance in KRAS-Mutated Lung Cancer Is Enabled by Stem-like Properties Mediated by an Osteopontin-EGFR Pathway.
abstract: Lung cancers with activating KRAS mutations are characterized by treatment resistance and poor prognosis. In particular, the basis for their resistance to radiation therapy is poorly understood. Here, we describe a radiation resistance phenotype conferred by a stem-like subpopulation characterized by mitosis-like condensed chromatin (MLCC), high CD133 expression, invasive potential, and tumor-initiating properties. Mechanistic investigations defined a pathway involving osteopontin and the EGFR in promoting this phenotype. Osteopontin/EGFR-dependent MLCC protected cells against radiation-induced DNA double-strand breaks and repressed putative negative regulators of stem-like properties, such as CRMP1 and BIM. The MLCC-positive phenotype defined a subset of KRAS-mutated lung cancers that were enriched for co-occurring genomic alterations in TP53 and CDKN2A. Our results illuminate the basis for the radiation resistance of KRAS-mutated lung cancers, with possible implications for prognostic and therapeutic strategies.Cancer Res; 77(8); 2018-28. ©2017 AACR.
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.|Jinan Municipal Center for Disease Control and Prevention, Shandong, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Lynnette
authors.initials: L
authors.lastname: Marcar
authors.affiliation: University of Colorado School of Medicine, Aurora, Colorado.|Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Josh
authors.initials: J
authors.lastname: Black
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Laboratory for Lipid Medicine and Technology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Xiangyong
authors.initials: X
authors.lastname: Li
authors.affiliation: Center for Computational Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Kshithija
authors.initials: K
authors.lastname: Nagulapalli
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Raymond H
authors.initials: RH
authors.lastname: Mak
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Cyril H
authors.initials: CH
authors.lastname: Benes
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Hong
authors.affiliation: Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.|OncoRay National Center for Radiation Research in Oncology, Dresden, Germany.|Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.|Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.|Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.|Cancer Consortium (DKTK) Partner Site Dresden and German Cancer Research Center (DKFZ) Heidelberg, Dresden, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Gurtner
authors.affiliation: Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.|OncoRay National Center for Radiation Research in Oncology, Dresden, Germany.|Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.|Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.|Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.|Cancer Consortium (DKTK) Partner Site Dresden and German Cancer Research Center (DKFZ) Heidelberg, Dresden, Germany.
authors.forename: Mechthild
authors.initials: M
authors.lastname: Krause
authors.affiliation: Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.|OncoRay National Center for Radiation Research in Oncology, Dresden, Germany.|Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.|Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.|Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.|Cancer Consortium (DKTK) Partner Site Dresden and German Cancer Research Center (DKFZ) Heidelberg, Dresden, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Baumann
authors.affiliation: Laboratory for Lipid Medicine and Technology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Jing X
authors.initials: JX
authors.lastname: Kang
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Johnathan R
authors.initials: JR
authors.lastname: Whetstine
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. hwillers@partners.org.
authors.forename: Henning
authors.initials: H
authors.lastname: Willers
mesh_terms: D000072283:A549 Cells; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D053495:Osteopontin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics; D015398:Signal Transduction
chemical_list: C117307:KRAS protein, human; C506895:SPP1 protein, human; D053495:Osteopontin; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras)