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

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.

Targeting the DNA-PK complex: Its rationale use in cancer and HIV-1 infection

“…CC-115 has been tested in vitro on a wide variety of cancer cell lines comprising lymphomas, leukemias, hepatocellular carcinoma, breast, lung, head and neck cancer cell-lines. These studies suggest that CC-115 is efficient when used in monotherapy in ATM deficient cells, or in combination of other DNA-damaging agents in some cancers [38].…”

Signal Transduction Pathways in Breast Cancer: The Important Role of PI3K/Akt/mTOR

“…Low levels of DNA-PKcs protein expression were related to higher tumour grade, dedifferentiation and mitotic index, and poor survival [73,109]. CC-115, a dual inhibitor of mTOR and DNA-PKcs, has been shown to inhibit cell growth in vitro by blocking DDR pathways, thus inducing apoptosis in many cancer lines, including breast cancer cells [110]. Currently, a phase I clinical trial with CC-115 is ongoing.…”

Moving From Poly (ADP-Ribose) Polymerase Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy

“…76 A number of novel DNA-PK inhibitors have recently entered clinical development, as monotherapy, in combination with radiotherapy or liposomal doxorubicin, or using a dual inhibitor of DNA-PK and mammalian target of rapamycin. 77 POLQ is required for MMEJ (alt-NHEJ), which is upregulated in many cancers promoting error-prone repair and potentially cancer evolution. POLQ-dependent MMEJ repair is particularly important in HRR-deficient cancers (eg, BRCA1/2-mutated tumors).…”