PMID- 29088817
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20191120
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 8
IP  - 43
DP  - 2017 Sep 26
TI  - CC-115, a dual inhibitor of mTOR kinase and DNA-PK, blocks DNA damage repair 
      pathways and selectively inhibits ATM-deficient cell growth in vitro.
PG  - 74688-74702
LID - 10.18632/oncotarget.20342 [doi]
AB  - CC-115, a selective dual inhibitor of the mammalian target of rapamycin (mTOR) 
      kinase and DNA-dependent protein kinase (DNA-PK), is undergoing Phase 1 clinical 
      studies. Here we report the characterization of DNA-PK inhibitory activity of 
      CC-115 in cancer cell lines. CC-115 inhibits auto-phosphorylation of the 
      catalytic subunit of DNA-PK (DNA-PKcs) at the S2056 site (pDNA-PK S2056), leading 
      to blockade of DNA-PK-mediated non-homologous end joining (NHEJ). CC-115 also 
      indirectly reduces the phosphorylation of ataxia-telangiectasia mutated kinase 
      (ATM) at S1981 and its substrates as well as homologous recombination (HR). The 
      mTOR kinase and DNA-PK inhibitory activity of CC-115 leads to not only potent 
      anti-tumor activity against a large panel of hematopoietic and solid cancer cell 
      lines but also strong induction of apoptosis in a subset of cancer lines. 
      Mechanistically, CC-115 prevents NHEJ by inhibiting the dissociation of DNA-PKcs, 
      X-ray repair cross-complementing protein 4 (XRCC4), and DNA ligase IV from DNA 
      ends. CC-115 inhibits colony formation of ATM-deficient cells more potently than 
      ATM-proficient cells, indicating that inhibition of DNA-PK is synthetically 
      lethal with the loss of functional ATM. In conclusion, CC-115 inhibits both mTOR 
      signaling and NHEJ and HR by direct inhibition of DNA-PK. The mechanistic data 
      not only provide selection of potential pharmacodynamic (PD) markers but also 
      support CC-115 clinical development in patients with ATM-deficient tumors.
FAU - Tsuji, Toshiya
AU  - Tsuji T
AD  - Oncology Research, Celgene Corporation, San Diego, CA 92121, USA.
FAU - Sapinoso, Lisa M
AU  - Sapinoso LM
AD  - Oncology Research, Celgene Corporation, San Diego, CA 92121, USA.
FAU - Tran, Tam
AU  - Tran T
AD  - Oncology Research, Celgene Corporation, San Diego, CA 92121, USA.
FAU - Gaffney, Bonny
AU  - Gaffney B
AD  - Oncology Research, Celgene Corporation, San Diego, CA 92121, USA.
FAU - Wong, Lilly
AU  - Wong L
AD  - Oncology Research, Celgene Corporation, San Diego, CA 92121, USA.
FAU - Sankar, Sabita
AU  - Sankar S
AD  - Oncology Research, Celgene Corporation, San Diego, CA 92121, USA.
FAU - Raymon, Heather K
AU  - Raymon HK
AD  - Pharmacology, Celgene Corporation, San Diego, CA 92121, USA.
FAU - Mortensen, Deborah S
AU  - Mortensen DS
AD  - Medicinal Chemistry, Celgene Corporation, San Diego, CA 92121, USA.
FAU - Xu, Shuichan
AU  - Xu S
AD  - Oncology Research, Celgene Corporation, San Diego, CA 92121, USA.
LA  - eng
PT  - Journal Article
DEP - 20170818
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
PMC - PMC5650372
OTO - NOTNLM
OT  - ATM
OT  - DNA damage repair
OT  - DNA-PK
OT  - mTOR kinase
COIS- CONFLICTS OF INTEREST All authors are currently employees of Celgene, except S. 
      Sankar, who was an employee of Celgene at the time of her contribution to this 
      work.
EDAT- 2017/11/02 06:00
MHDA- 2017/11/02 06:01
PMCR- 2017/09/26
CRDT- 2017/11/02 06:00
PHST- 2017/02/17 00:00 [received]
PHST- 2017/07/25 00:00 [accepted]
PHST- 2017/11/02 06:00 [entrez]
PHST- 2017/11/02 06:00 [pubmed]
PHST- 2017/11/02 06:01 [medline]
PHST- 2017/09/26 00:00 [pmc-release]
AID - 20342 [pii]
AID - 10.18632/oncotarget.20342 [doi]
PST - epublish
SO  - Oncotarget. 2017 Aug 18;8(43):74688-74702. doi: 10.18632/oncotarget.20342. 
      eCollection 2017 Sep 26.