The Potential for Targeting G2/M Cell Cycle Checkpoint Kinases in Enhancing the Efficacy of Radiotherapy
Abstract
:Simple Summary
Abstract
1. Introduction
2. The Cellular DNA Damage Response (DDR)
3. Roles of Chk1 and Wee1
4. Targeting Cell Cycle Checkpoint Kinases
4.1. Development and Progression of Chk1 Inhibitors
4.2. Development and Progression of Wee1 Inhibitors
4.3. Chk1 Inhibitor Preclinical Studies
Inhibitor | Cells | Observations | Ref |
---|---|---|---|
AZD7762 | UMSCC-1, UMSCC-6, UMSCC-47 | UMSCC-1 (DER = 2.94) Increased γH2AX staining at 4 h Increased neutral comet tail moment at 48 h Increased apoptotic cell death | [97] |
AZD7762 | MiaPaCa-2 | γH2AX foci persists up to 24 h Reduced RAD51 foci formation at 26–30 h Reduced HR in DR-GFP assay Increased sensitivity in vivo | [102] |
AZD7762(+Olaparib) | MiaPaCa-2, MPanc-96, HCT116, H460, CCL-241 | No radiosensitisation to p53-wt or epithelial cells AZD7762 (DER = 1.5–2.0), plus olaparib (DER = 2.4–3.0) Increased γH2AX foci at 16–24 h | [99] |
AZD7762 | MCF-7, A549, H460, HT29, 1522, PC-Sw, SF-295, DU145, MiaPaCa-2 | p53-mut (DER = 1.6–1.7) p53-wt (DER = 1.1–1.2) Increased γH2AX expression at 8 and 24 h Increased nuclear fragmentation at 24–72 h Increased sensitivity in vivo | [103] |
CCT244747 | RT112, T24, Cal-27, hTertRPE1 | DER = 1.33–1.62 Increase in pan-γH2AX and abnormal nuclei Increased cleaved PARP-1 and caspase-3 at 48 h Increased sensitivity in vivo with Cal-27 xenografts | [104] |
CHIR-124 | HCT116 | Radiosensitisation irrespective of p53 status Radiosensitisation in p21, Chk2 and MAD2 KO cell lines Increased mitotic catastrophe in p53-mut | [101] |
LY2606368 | UMSCC-1, UMSCC-47 | Increase in S phase cells Increased γH2AX, caspase-3 and apoptosis at 48 h Increased sensitivity in vivo xenografts | [105] |
MK-8776 | MDA-MB-231, BT-549, Cal-51 | Radiosensitivity irrespective of p53 status Increased γH2AX staining at 2 h Cell death via autophagy Radiosensitivity in vivo | [95] |
MK-8776 | H1299, Calu-6, FaDu, A549, H460 | No radiosensitisation in p53-proficient cells Increase in γH2AX/53BP1 foci and reduced RAD51 activity | [98] |
MK-8776 | MiaPaCa-2, BxPC-3, AsPC-1, Capan-1 | Reduction in RAD51 foci formation | [106] |
SAR-020106 | LN405, T98G, A172, DBTRG, P0297, P0306 | 1.7–2.1 fold increase in SSBs at 24 h | [96] |
SAR-020106 | Cal-27, HeLa, HN6, A549, MEF | No radiosensitisation in p53-proficient cells Reduced γH2AX/RAD51 foci colocalization Unsuccessful cytokinesis and increase in aneuploid cells Increased apoptosis at 24 h Radiosensitivity in vivo, with increased TUNEL staining | [100] |
UCN-01 | HeLa | Prolonged mitosis due to SAC activation | [107] |
UCN-01 MK-8776 | HeLa | UCN-01 (DER = 1.07–1.13) MK-8776 (DER = 1.22–1.39) No alterations in γH2AX/RAD51 foci Increased centromere numbers and time spent in mitosis | [108] |
4.4. Wee1 Inhibitor Preclinical Studies
4.5. Chk1/Wee1 Inhibitors in Combination with Protons and Higher LET Radiation
4.6. Clinical Trials of Chk1/Wee1 Inhibitors in Combination with Radiotherapy
5. Conclusions and Future Directions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Inhibitor | Cells | Observations | Ref |
---|---|---|---|
MK-1775 | A549, H1299, Calu-6, H460, CCD16, MCF-7, MDA-MB-231, MCF-10A, PC3, LnCaP | No radiosensitivity in p53-proficient cells Radiosensitivity in p53-deficient cells (DER = 1.2–1.5) Increased γH2AX Pre-mature mitotic entry at 4 h Increased micronuclei Radiosensitivity in vivo | [114] |
MK-1775 | UMSCC-47, SSC-25, SSC-15, Cal-27 | Radiosensitisation irrespective of p53 status p53-containing cells increased mitotic catastrophe p53-deficient cells increased apoptosis | [115] |
MK-1775 | U251, U87, T98G, G179, G144, astrocytes | Radiosensitisation irrespective of p53 status (DER = 1.2–1.3) No radiosensitivity of stem cells Slight radioprotective in astrocytes Increase γH2AX expression at 10 h Increase in micronuclei formation Radiosensitivity in vivo | [116] |
MK-1775 | VUMC-DIPG-A, E98 | γH2AX and 53BP1 foci up to 72 h | [117] |
MK-1775 | MiaPaCa-2, Panc-1, Capan-1, DLD-1 | Increased γH2AX foci No radiosensitisation in HR-deficient cells Radiosensitivity in vivo, decreased RAD51 foci formation | [118] |
MK-1775 | HepG2, Hep3B, Huh7 | Radiosensitivity (DER = 1.22–1.38) Increased pan-nuclear γH2AX at 16 h Nucleotide supplementation reversed radiosensitivity Pre-mature mitotic entry | [119] |
MK-1775 | Calu-6, H23, H1730 | Radiosensitivity (DER = 1.23–1.43) Nucleotide supplementation reversed radiosensitivity Pre-mature mitotic entry Radiosensitivity in vivo | [120] |
MK-1775 | HeLa, siHa | Increased γH2AX expression Increased caspase activity and apoptosis at 48–72 h Radiosensitivity in vivo; increased yH2AX/TUNEL, decreased Ki67 | [121] |
MK-1775 | OE33, SK4, KYSE30, AGS | Radiosensitivity (DER = 1.23–3.14) Increased γH2AX expression at 24 h Increased mitotic catastrophe Radiosensitivity in vivo; increased mitotic catastrophe | [122] |
MK-1775 | Jurkat, MOLT-4 | No radiosensitivity in normal cells Increased γH2AX staining | [123] |
MK-1775 PD0166285 | BJ fibroblasts, murine cardiomyocytes, MCF-7, HeLa, MDA-MB-231, SK-BR-3, T47D | Radiosensitisation in p53-deficient cells Increased γH2AX foci Reduced 53BP1 foci Reduced HR proficiency via DR-GFP | [124] |
PD0166285 | PA-1, HT29, HeLa, HCT8, HCT116, DLD-1, H460, C26 | Radiosensitisation in p53-deficient cells (DER = 1.23–1.38) Increased mitotic index | [85] |
PD0166285 | H1299, MCF-7 | Radiosensitisation in p53-deficient H1299 cells (DER = 1.25) but not in p53-expressing H1299 cells (DER = 1.09) | [113] |
PD0166285 | MG-63, U2OS, SaOS-2, Hum31, Hum54 | No radiosensitisation in normal cells Increased γH2AX foci at 24 h Increased caspase activity and apoptosis | [125] |
PD0166285 | KYSE70, KYSE150, KYSE410, KYSE450, KYSE510, TE1, TE7, EC1, HEEC | Radiosensitivity (DER = 1.37–1.60) Increased γH2AX foci and SSBs at 24 h Decreased RAD51 foci formation Increased mitotic catastrophe, caspase activity and apoptosis Radiosensitivity in vivo; decreased RAD51 | [126] |
PD0166285 | U251-MG, U118-MG, U87-MG, U373-MG, VU147, VU148, E98, fibroblasts, astrocytes | Radiosensitivity (DER = 1.19–1.95) Increased radiosensitivity of primary stem-like cells Increase γH2AX foci Increase in pre-mature mitotic entry and nuclear fragmentation Radiosensitivity in vivo | [127] |
Target | Inhibitor | Cells | Radiotherapy Type | Observations | Ref |
---|---|---|---|---|---|
Chk1 | PF-00477736 | MDA-MB-231, Hs578T | 280 MeV protons | Enhanced radiosensitivity of protons versus X-rays | [135] |
Chk1 | UCN-01 | Stem-like subpopulation of SQ20B | 11.4 MeV carbon ions (184 keV/µm) | Enhanced radiosensitisation with carbon ions versus X-rays | [139] |
Chk1/Chk2 | AZD7762 | A549, H1299 | 80 MeV carbon ions (50 keV/µm) | Equal radiosensitisation with carbon ions and X-rays in A549, but enhanced radiosensitisation with carbon ions in H1299 | [138] |
Chk1/Chk2 | LY2606368 | Colo357, MiaPaCa-2 | 150 MeV protons (3.7 keV/µm) | Enhanced radiosensitivity of X-rays versus protons | [136] |
Wee1 | MK1775 | H1299 | 290 MeV carbon ions (50 keV/µm) | Equal radiosensitisation with carbon ions and X-rays | [137] |
Target | Identifier | Phase | Inhibitor/Treatment | Tumour | Status/Outcomes | Ref |
---|---|---|---|---|---|---|
Chk1/Chk2 | NCT02555644 | Ib | LY2606368 plus cisplatin/cetuximab and RT | HNSCC | Completed in 2019 | |
Wee1 | NCT03345784 | I | AZD1775 plus cisplatin and RT | Cervical, upper viaginal, uterine | Closed prematurely; limiting toxicities | |
Wee1 | NCT01922076 | I | AZD1775 and RT | DIPG | Completed in 2022 | |
Wee1 | NCT05765812 | I/II | Debio 0123 plus TMZ and RT | GBM | Active/recruiting | |
Wee1 | NCT01849146 | I | AZD1775 plus TMZ and RT | GBM | Active/not recruiting | |
Wee1 | NCT03028766 | I | AZD1775 plus cisplatin and RT | HNSCC | Completed in 2021; poor recruitment and toxicities | |
Wee1 | NCT02585973 | Ib | AZD1775 plus cisplatin and RT | HNSCC | Completed in 2021; dose-limiting toxicities | [140] |
Wee1 | NCT04460937 | I | AZD1775 and RT | Oesophageal and gastrooesophageal | Active/not recruiting | |
Wee1 | NCT02037230 | I | MK1775 plus gemcitabine and RT | PDAC | Completed in 2018; treatment well tolerated and improved overall survival | [141] |
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Melia, E.; Parsons, J.L. The Potential for Targeting G2/M Cell Cycle Checkpoint Kinases in Enhancing the Efficacy of Radiotherapy. Cancers 2024, 16, 3016. https://doi.org/10.3390/cancers16173016
Melia E, Parsons JL. The Potential for Targeting G2/M Cell Cycle Checkpoint Kinases in Enhancing the Efficacy of Radiotherapy. Cancers. 2024; 16(17):3016. https://doi.org/10.3390/cancers16173016
Chicago/Turabian StyleMelia, Emma, and Jason L. Parsons. 2024. "The Potential for Targeting G2/M Cell Cycle Checkpoint Kinases in Enhancing the Efficacy of Radiotherapy" Cancers 16, no. 17: 3016. https://doi.org/10.3390/cancers16173016