Abstract:CC-115 is a dual inhibitor of the mechanistic target of rapamycin (mTOR) kinase and the DNA-dependent protein kinase (DNA-PK) that is currently being studied in phase I/II clinical trials. DNA-PK is essential for the repair of DNA-double strand breaks (DSB). Radiotherapy is frequently used in the palliative treatment of metastatic melanoma patients and induces DSBs. Melanoma cell lines and healthy-donor skin fibroblast cell lines were treated with CC-115 and ionizing irradiation (IR). Apoptosis, necrosis, and … Show more
“…Multiple inhibitors of each of the kinases are currently being investigated in clinical trials, such as CC-115, a dual inhibitor of both DNA-PK and mTOR (NCT02833883, NCT01353625), ATM-inhibitor AZD0156 (NCT02588105), and ATR-inhibitor VE-822 (synonyms: berzosertib, VX-970, M6620) (NCT02487095, NCT02589522), [ 3 ]. Favorable effects for a combination of IR with CC-115 have already been described in melanoma cells, where an increased radiosensitivity was observed in malignant cells [ 19 ]. Additionally, KI targeting DNA single-strand break repair pathways such as PARP1 and PARP2 showed promising results when PARP inhibitors were combined with irradiation [ 20 ].…”
(1) Kinase inhibitors (KI) targeting components of the DNA damage repair pathway are a promising new type of drug. Combining them with ionizing radiation therapy (IR), which is commonly used for treatment of head and neck tumors, could improve tumor control, but could also increase negative side effects on surrounding normal tissue. (2) The effect of KI of the DDR (ATMi: AZD0156; ATRi: VE-822, dual DNA-PKi/mTORi: CC-115) in combination with IR on HPV-positive and HPV-negative HNSCC and healthy skin cells was analyzed. Cell death and cell cycle arrest were determined using flow cytometry. Additionally, clonogenic survival and migration were analyzed. (3) Studied HNSCC cell lines reacted differently to DDRi. An increase in cell death for all of the malignant cells could be observed when combining IR and KI. Healthy fibroblasts were not affected by simultaneous treatment. Migration was partially impaired. Influence on the cell cycle varied between the cell lines and inhibitors; (4) In conclusion, a combination of DDRi with IR could be feasible for patients with HNSCC. Side effects on healthy cells are expected to be limited to normal radiation-induced response. Formation of metastases could be decreased because cell migration is impaired partially. The treatment outcome for HPV-negative tumors tends to be improved by combined treatment.
“…Multiple inhibitors of each of the kinases are currently being investigated in clinical trials, such as CC-115, a dual inhibitor of both DNA-PK and mTOR (NCT02833883, NCT01353625), ATM-inhibitor AZD0156 (NCT02588105), and ATR-inhibitor VE-822 (synonyms: berzosertib, VX-970, M6620) (NCT02487095, NCT02589522), [ 3 ]. Favorable effects for a combination of IR with CC-115 have already been described in melanoma cells, where an increased radiosensitivity was observed in malignant cells [ 19 ]. Additionally, KI targeting DNA single-strand break repair pathways such as PARP1 and PARP2 showed promising results when PARP inhibitors were combined with irradiation [ 20 ].…”
(1) Kinase inhibitors (KI) targeting components of the DNA damage repair pathway are a promising new type of drug. Combining them with ionizing radiation therapy (IR), which is commonly used for treatment of head and neck tumors, could improve tumor control, but could also increase negative side effects on surrounding normal tissue. (2) The effect of KI of the DDR (ATMi: AZD0156; ATRi: VE-822, dual DNA-PKi/mTORi: CC-115) in combination with IR on HPV-positive and HPV-negative HNSCC and healthy skin cells was analyzed. Cell death and cell cycle arrest were determined using flow cytometry. Additionally, clonogenic survival and migration were analyzed. (3) Studied HNSCC cell lines reacted differently to DDRi. An increase in cell death for all of the malignant cells could be observed when combining IR and KI. Healthy fibroblasts were not affected by simultaneous treatment. Migration was partially impaired. Influence on the cell cycle varied between the cell lines and inhibitors; (4) In conclusion, a combination of DDRi with IR could be feasible for patients with HNSCC. Side effects on healthy cells are expected to be limited to normal radiation-induced response. Formation of metastases could be decreased because cell migration is impaired partially. The treatment outcome for HPV-negative tumors tends to be improved by combined treatment.
“…for the resistance of tumor cells to radiotherapy. 39 In this work, no significant effect of IR on HCC cells was found responsive to the high expression of PAK7, but the viability of HCC cells was suppressed in low PAK7 expression, which provided the possibility that PAK7 in high expression could enhance the activity of DNA repair-related pathway. During the DSB resulted from various factors, H2AX is phosphorylated into g-H2AX, which, thus, has been taken as an indicator for DNA damage and repair, and its upregulation indicated the exacerbation of DNA damage.…”
Objective: In light of the upregulation of p21-activated kinase (PAK7) in a variety of cancers, including hepatocellular carcinoma (HCC), we aimed to investigate the effect of PAK7 on the sensitivity of HCC cells to radiotherapy. Methods: PAK7 expression was determined in normal adult liver epithelial THLE-2 and human HCC cell lines. The effect of ionizing radiation (IR) on the HCC cell viability was evaluated by Sulforhodamine B (SRB) assay. HCC cell lines Mahlavu and Huh7 were chosen to assess the effect of PAK7 shRNAs on the viability, clone formation, apoptosis, cycle distribution and γ-H2AX expression after exposure to IR. Results: As compared to THLE-2 cells, PAK7 was upregulated in poorly differentiated Mahlavu and SK-Hep-1 cells, but moderately or lowly expressed in well-differentiated Huh7 and HepG2 cells. HCC cells with moderate or low expression of PAK7 presented a decreased viability at 2 Gy IR, which had no significant effect on PAK7high HCC cells. Mahlavu and Huh7 cells transfected with PAK7 shRNAs showed increased inhibitory effect of IR on viability. In addition, PAK7 shRNAs reduced clone formation, facilitated the cell apoptosis, arrested cells at G2/M phase, and increased γ-H2AX expression. Moreover, changes above were more evident in the HCC cells co-treated with IR and PAK7 shRNAs. Conclusion: PAK7 downregulation could inhibit the viability, promote the apoptosis, arrest cells in G2/M phase, and induce the DNA damage in HCC cells, thereby enhancing the radiosensitivity in HCC.
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