PMID- 27135971
OWN - NLM
STAT- MEDLINE
DCOM- 20170508
LR  - 20190816
IS  - 1938-5404 (Electronic)
IS  - 0033-7587 (Print)
IS  - 0033-7587 (Linking)
VI  - 185
IP  - 5
DP  - 2016 May
TI  - Torin2 Suppresses Ionizing Radiation-Induced DNA Damage Repair.
PG  - 527-38
LID - 10.1667/RR14373.1 [doi]
AB  - Several classes of inhibitors of the mammalian target of rapamycin (mTOR) have 
      been developed based on its central role in sensing growth factor and nutrient 
      levels to regulate cellular metabolism. However, its ATP-binding site closely 
      resembles other phosphatidylinositol 3-kinase-related kinase (PIKK) family 
      members, resulting in reactivity with these targets that may also be 
      therapeutically useful. The ATP-competitive mTOR inhibitor, Torin2, shows 
      biochemical activity against the DNA repair-associated proteins ATM, ATR and 
      DNA-PK, which raises the possibility that Torin2 and related compounds might 
      radiosensitize cancerous tumors. In this study Torin2 was also found to enhance 
      ionizing radiation-induced cell killing in conditions where ATM was dispensable, 
      confirming the requirement for multiple PIKK targets. Moreover, Torin2 did not 
      influence the initial appearance of gamma-H2AX foci after irradiation but 
      significantly delayed the disappearance of radiation-induced gamma-H2AX foci, 
      indicating a DNA repair defect. Torin2 increased the number of radiation-induced 
      S-phase specific chromosome aberrations and reduced the frequency of 
      radiation-induced CtIP and Rad51 foci formation, suggesting that Torin2 works by 
      blocking homologous recombination (HR)-mediated DNA repair resulting in an 
      S-phase specific DNA repair defect. Accordingly, Torin2 reduced HR-mediated 
      repair of I-Sce1-induced DNA damage and contributed to replication fork stalling. 
      We conclude that radiosensitization of tumor cells by Torin2 is associated with 
      disrupting ATR- and ATM-dependent DNA damage responses. Our findings support the 
      concept of developing combination cancer therapies that incorporate ionizing 
      radiation therapy and Torin2 or compounds with similar properties.
FAU - Udayakumar, Durga
AU  - Udayakumar D
AD  - a   Department of Radiation Oncology and.
AD  - c   Department of Radiation Oncology, The Houston Methodist Research Institute, 
      Houston, Texas 77030; and.
FAU - Pandita, Raj K
AU  - Pandita RK
AD  - a   Department of Radiation Oncology and.
AD  - c   Department of Radiation Oncology, The Houston Methodist Research Institute, 
      Houston, Texas 77030; and.
FAU - Horikoshi, Nobuo
AU  - Horikoshi N
AD  - a   Department of Radiation Oncology and.
AD  - c   Department of Radiation Oncology, The Houston Methodist Research Institute, 
      Houston, Texas 77030; and.
FAU - Liu, Yan
AU  - Liu Y
AD  - d   Center for Thoracic Oncology, Dana Farber Cancer Institute and.
FAU - Liu, Qingsong
AU  - Liu Q
AD  - e   Department of Biological Chemistry and Molecular Pharmacology, Harvard 
      Medical School, Boston, Massachusetts 02115.
FAU - Wong, Kwok-Kin
AU  - Wong KK
AD  - d   Center for Thoracic Oncology, Dana Farber Cancer Institute and.
FAU - Hunt, Clayton R
AU  - Hunt CR
AD  - a   Department of Radiation Oncology and.
AD  - c   Department of Radiation Oncology, The Houston Methodist Research Institute, 
      Houston, Texas 77030; and.
FAU - Gray, Nathanael S
AU  - Gray NS
AD  - e   Department of Biological Chemistry and Molecular Pharmacology, Harvard 
      Medical School, Boston, Massachusetts 02115.
FAU - Minna, John D
AU  - Minna JD
AD  - b   Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical 
      Center, Dallas, Texas 75390;
FAU - Pandita, Tej K
AU  - Pandita TK
AD  - a   Department of Radiation Oncology and.
AD  - c   Department of Radiation Oncology, The Houston Methodist Research Institute, 
      Houston, Texas 77030; and.
FAU - Westover, Kenneth D
AU  - Westover KD
AD  - a   Department of Radiation Oncology and.
LA  - eng
GR  - P50 CA070907/CA/NCI NIH HHS/United States
GR  - R01 CA129537/CA/NCI NIH HHS/United States
GR  - R01 GM109768/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20160502
PL  - United States
TA  - Radiat Res
JT  - Radiation research
JID - 0401245
RN  - 0 
      (9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one)
RN  - 0 (H2AX protein, human)
RN  - 0 (Histones)
RN  - 0 (Naphthyridines)
RN  - 0 (Radiation-Sensitizing Agents)
SB  - IM
MH  - Cell Line
MH  - Cell Survival/drug effects/radiation effects
MH  - Chromosome Aberrations/drug effects/radiation effects
MH  - DNA Breaks, Double-Stranded/drug effects/radiation effects
MH  - *DNA Damage
MH  - DNA Repair/*drug effects/*radiation effects
MH  - DNA Replication/drug effects/radiation effects
MH  - G2 Phase/drug effects/radiation effects
MH  - Histones/metabolism
MH  - Homologous Recombination/drug effects/radiation effects
MH  - Humans
MH  - Kinetics
MH  - Naphthyridines/*pharmacology
MH  - Radiation-Sensitizing Agents/*pharmacology
MH  - S Phase/drug effects/radiation effects
PMC - PMC4922265
MID - NIHMS788296
EDAT- 2016/05/03 06:00
MHDA- 2017/05/10 06:00
PMCR- 2017/05/02
CRDT- 2016/05/03 06:00
PHST- 2016/05/03 06:00 [entrez]
PHST- 2016/05/03 06:00 [pubmed]
PHST- 2017/05/10 06:00 [medline]
PHST- 2017/05/02 00:00 [pmc-release]
AID - 10.1667/RR14373.1 [doi]
PST - ppublish
SO  - Radiat Res. 2016 May;185(5):527-38. doi: 10.1667/RR14373.1. Epub 2016 May 2.