title: MutT Homolog 1 (MTH1) maintains multiple KRAS-driven pro-malignant pathways.
abstract: Oncogenic RAS promotes production of reactive oxygen species (ROS), which mediate pro-malignant signaling but can also trigger DNA damage-induced tumor suppression. Thus RAS-driven tumor cells require redox-protective mechanisms to mitigate the damaging aspects of ROS. Here, we show that MutT Homolog 1 (MTH1), the mammalian 8-oxodGTPase that sanitizes oxidative damage in the nucleotide pool, is important for maintaining several KRAS-driven pro-malignant traits in a nonsmall cell lung carcinoma (NSCLC) model. MTH1 suppression in KRAS-mutant NSCLC cells impairs proliferation and xenograft tumor formation. Furthermore, MTH1 levels modulate KRAS-induced transformation of immortalized lung epithelial cells. MTH1 expression is upregulated by oncogenic KRAS and correlates positively with high KRAS levels in NSCLC human tumors. At a molecular level, in p53-competent KRAS-mutant cells, MTH1 loss provokes DNA damage and induction of oncogene-induced senescence. In p53-nonfunctional KRAS-mutant cells, MTH1 suppression does not produce DNA damage but reduces proliferation and leads to an adaptive decrease in KRAS expression levels. Thus, MTH1 not only enables evasion of oxidative DNA damage and its consequences, but can also function as a molecular rheostat for maintaining oncogene expression at optimal levels. Accordingly, our results indicate MTH1 is a novel and critical component of oncogenic KRAS-associated malignancy and its inhibition is likely to yield significant tumor-suppressive outcomes in KRAS-driven tumors.
authors.affiliation: Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA.
authors.forename: A
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA.
authors.forename: D G A
authors.initials: DG
authors.lastname: Burton
authors.affiliation: Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA.
authors.forename: K
authors.initials: K
authors.lastname: Halvorsen
authors.affiliation: Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA.
authors.forename: W
authors.initials: W
authors.lastname: Balkan
authors.affiliation: Geriatric Research, Education and Clinical Center, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL, USA.
authors.forename: T
authors.initials: T
authors.lastname: Reiner
authors.affiliation: 1] Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA [2] Geriatric Research, Education and Clinical Center, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL, USA [3] Sylvester Comprehensive Cancer Center, University of Miami Leonard M. Miller School of Medicine, FL, USA.
authors.forename: C
authors.initials: C
authors.lastname: Perez-Stable
authors.affiliation: 1] Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA [2] David and Sheila Fuente Graduate Program in Cancer Biology, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA.
authors.forename: A
authors.initials: A
authors.lastname: Cohen
authors.affiliation: Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA.
authors.forename: A
authors.initials: A
authors.lastname: Munoz
authors.affiliation: Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Giribaldi
authors.affiliation: Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Singh
authors.affiliation: 1] Sylvester Comprehensive Cancer Center, University of Miami Leonard M. Miller School of Medicine, FL, USA [2] Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Robbins
authors.affiliation: 1] Sylvester Comprehensive Cancer Center, University of Miami Leonard M. Miller School of Medicine, FL, USA [2] Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Nguyen
authors.affiliation: 1] Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA [2] Sylvester Comprehensive Cancer Center, University of Miami Leonard M. Miller School of Medicine, FL, USA.
authors.forename: P
authors.initials: P
authors.lastname: Rai
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D004249:DNA Damage; D045643:DNA Repair Enzymes / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D010744:Phosphoric Monoester Hydrolases; C078207:8-oxodGTPase; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D045643:DNA Repair Enzymes