title: Minor Changes in Expression of the Mismatch Repair Protein MSH2 Exert a Major Impact on Glioblastoma Response to Temozolomide.
abstract: Glioblastoma (GBM) is often treated with the cytotoxic drug temozolomide, but the disease inevitably recurs in a drug-resistant form after initial treatment. Here, we report that in GBM cells, even a modest decrease in the mismatch repair (MMR) components MSH2 and MSH6 have profound effects on temozolomide sensitivity. RNAi-mediated attenuation of MSH2 and MSH6 showed that such modest decreases provided an unexpectedly strong mechanism of temozolomide resistance. In a mouse xenograft model of human GBM, small changes in MSH2 were sufficient to suppress temozolomide-induced tumor regression. Using The Cancer Genome Atlas to analyze mRNA expression patterns in tumors from temozolomide-treated GBM patients, we found that MSH2 transcripts in primary GBM could predict patient responses to initial temozolomide therapy. In recurrent disease, the absence of microsatellite instability (the standard marker for MMR deficiency) suggests a lack of involvement of MMR in the resistant phenotype of recurrent disease. However, more recent studies reveal that decreased MMR protein levels occur often in recurrent GBM. In accordance with our findings, these reported decreases may constitute a mechanism by which GBM evades temozolomide sensitivity while maintaining microsatellite stability. Overall, our results highlight the powerful effects of MSH2 attenuation as a potent mediator of temozolomide resistance and argue that MMR activity offers a predictive marker for initial therapeutic response to temozolomide treatment.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts. Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: José L
authors.initials: JL
authors.lastname: McFaline-Figueroa
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Braun
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Monica
authors.initials: M
authors.lastname: Stanciu
authors.affiliation: Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Zachary D
authors.initials: ZD
authors.lastname: Nagel
authors.affiliation: Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Mazzucato
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Dewakar
authors.initials: D
authors.lastname: Sangaraju
authors.affiliation: Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Edvinas
authors.initials: E
authors.lastname: Cerniauskas
authors.affiliation: Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Kelly
authors.initials: K
authors.lastname: Barford
authors.affiliation: Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Amanda
authors.initials: A
authors.lastname: Vargas
authors.affiliation: Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Natalia
authors.initials: N
authors.lastname: Tretyakova
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Lees
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Hemann
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts. Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Forest M
authors.initials: FM
authors.lastname: White
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts. Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts. lsamson@mit.edu.
authors.forename: Leona D
authors.initials: LD
authors.lastname: Samson
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D002330:Carmustine / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000528:radiation effects; D015254:DNA Modification Methylases / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D055785:Gene Knockdown Techniques; D016158:Genes, p53; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D006801:Humans; D008810:Mice, Inbred C57BL; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000378:metabolism*; D011839:Radiation, Ionizing; D016019:Survival Analysis; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes; D002330:Carmustine; D000077204:Temozolomide