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 1 , Lisa M. Sapinoso 1 , Tam Tran 1 , Bonny Gaffney 1 , Lilly Wong 1 , Sabita Sankar 1 , Heather K. Raymon 2 , Deborah S. Mortensen 3 and Shuichan Xu 1 1 Oncology Research, Celgene Corporation, San Diego, CA 92121, USA 2 Pharmacology, Celgene Corporation, San Diego, CA 92121, USA 3 Medicinal 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.