Oncotarget

Research Papers:

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

Toshiya Tsuji, Lisa M. Sapinoso, Tam Tran, Bonny Gaffney, Lilly Wong, Sabita Sankar, Heather K. Raymon, Deborah S. Mortensen and Shuichan Xu _

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Oncotarget. 2017; 8:74688-74702. https://doi.org/10.18632/oncotarget.20342

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Abstract

Toshiya Tsuji1, Lisa M. Sapinoso1, Tam Tran1, Bonny Gaffney1, Lilly Wong1, Sabita Sankar1, Heather K. Raymon2, Deborah S. Mortensen3 and Shuichan Xu1

1Oncology Research, Celgene Corporation, San Diego, CA 92121, USA

2Pharmacology, Celgene Corporation, San Diego, CA 92121, USA

3Medicinal Chemistry, Celgene Corporation, San Diego, CA 92121, USA

Correspondence to:

Shuichan Xu, email: sxu@celgene.com

Toshiya Tsuji, email: ttsuji@celgene.com

Keywords: mTOR kinase, DNA-PK, DNA damage repair, ATM

Received: February 17, 2017     Accepted: July 25, 2017     Published: August 18, 2017

ABSTRACT

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.


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