Small-Molecule Polθ Inhibitors Provide Safe and Effective Tumor Radiosensitization in Preclinical Models
DNA polymerase theta (Polθ, encoded by the POLQ gene) is a DNA repair enzyme critical for microhomology mediated end joining (MMEJ). Polθ has limited expression in normal tissues but is frequently overexpressed in cancer cells and, therefore, represents an ideal target for tumor-specific radiosensit...
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| Published in: | Clinical cancer research Vol. 29; no. 8; p. 1631 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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United States
14.04.2023
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| ISSN: | 1557-3265, 1557-3265 |
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| Abstract | DNA polymerase theta (Polθ, encoded by the POLQ gene) is a DNA repair enzyme critical for microhomology mediated end joining (MMEJ). Polθ has limited expression in normal tissues but is frequently overexpressed in cancer cells and, therefore, represents an ideal target for tumor-specific radiosensitization. In this study we evaluate whether targeting Polθ with novel small-molecule inhibitors is a feasible strategy to improve the efficacy of radiotherapy.
We characterized the response to Polθ inhibition in combination with ionizing radiation in different cancer cell models in vitro and in vivo.
Here, we show that ART558 and ART899, two novel and specific allosteric inhibitors of the Polθ DNA polymerase domain, potently radiosensitize tumor cells, particularly when combined with fractionated radiation. Importantly, noncancerous cells were not radiosensitized by Polθ inhibition. Mechanistically, we show that the radiosensitization caused by Polθ inhibition is most effective in replicating cells and is due to impaired DNA damage repair. We also show that radiosensitization is still effective under hypoxia, suggesting that these inhibitors may help overcome hypoxia-induced radioresistance. In addition, we describe for the first time ART899 and characterize it as a potent and specific Polθ inhibitor with improved metabolic stability. In vivo, the combination of Polθ inhibition using ART899 with fractionated radiation is well tolerated and results in a significant reduction in tumor growth compared with radiation alone.
These results pave the way for future clinical trials of Polθ inhibitors in combination with radiotherapy. |
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| AbstractList | DNA polymerase theta (Polθ, encoded by the POLQ gene) is a DNA repair enzyme critical for microhomology mediated end joining (MMEJ). Polθ has limited expression in normal tissues but is frequently overexpressed in cancer cells and, therefore, represents an ideal target for tumor-specific radiosensitization. In this study we evaluate whether targeting Polθ with novel small-molecule inhibitors is a feasible strategy to improve the efficacy of radiotherapy.
We characterized the response to Polθ inhibition in combination with ionizing radiation in different cancer cell models in vitro and in vivo.
Here, we show that ART558 and ART899, two novel and specific allosteric inhibitors of the Polθ DNA polymerase domain, potently radiosensitize tumor cells, particularly when combined with fractionated radiation. Importantly, noncancerous cells were not radiosensitized by Polθ inhibition. Mechanistically, we show that the radiosensitization caused by Polθ inhibition is most effective in replicating cells and is due to impaired DNA damage repair. We also show that radiosensitization is still effective under hypoxia, suggesting that these inhibitors may help overcome hypoxia-induced radioresistance. In addition, we describe for the first time ART899 and characterize it as a potent and specific Polθ inhibitor with improved metabolic stability. In vivo, the combination of Polθ inhibition using ART899 with fractionated radiation is well tolerated and results in a significant reduction in tumor growth compared with radiation alone.
These results pave the way for future clinical trials of Polθ inhibitors in combination with radiotherapy. DNA polymerase theta (Polθ, encoded by the POLQ gene) is a DNA repair enzyme critical for microhomology mediated end joining (MMEJ). Polθ has limited expression in normal tissues but is frequently overexpressed in cancer cells and, therefore, represents an ideal target for tumor-specific radiosensitization. In this study we evaluate whether targeting Polθ with novel small-molecule inhibitors is a feasible strategy to improve the efficacy of radiotherapy.PURPOSEDNA polymerase theta (Polθ, encoded by the POLQ gene) is a DNA repair enzyme critical for microhomology mediated end joining (MMEJ). Polθ has limited expression in normal tissues but is frequently overexpressed in cancer cells and, therefore, represents an ideal target for tumor-specific radiosensitization. In this study we evaluate whether targeting Polθ with novel small-molecule inhibitors is a feasible strategy to improve the efficacy of radiotherapy.We characterized the response to Polθ inhibition in combination with ionizing radiation in different cancer cell models in vitro and in vivo.EXPERIMENTAL DESIGNWe characterized the response to Polθ inhibition in combination with ionizing radiation in different cancer cell models in vitro and in vivo.Here, we show that ART558 and ART899, two novel and specific allosteric inhibitors of the Polθ DNA polymerase domain, potently radiosensitize tumor cells, particularly when combined with fractionated radiation. Importantly, noncancerous cells were not radiosensitized by Polθ inhibition. Mechanistically, we show that the radiosensitization caused by Polθ inhibition is most effective in replicating cells and is due to impaired DNA damage repair. We also show that radiosensitization is still effective under hypoxia, suggesting that these inhibitors may help overcome hypoxia-induced radioresistance. In addition, we describe for the first time ART899 and characterize it as a potent and specific Polθ inhibitor with improved metabolic stability. In vivo, the combination of Polθ inhibition using ART899 with fractionated radiation is well tolerated and results in a significant reduction in tumor growth compared with radiation alone.RESULTSHere, we show that ART558 and ART899, two novel and specific allosteric inhibitors of the Polθ DNA polymerase domain, potently radiosensitize tumor cells, particularly when combined with fractionated radiation. Importantly, noncancerous cells were not radiosensitized by Polθ inhibition. Mechanistically, we show that the radiosensitization caused by Polθ inhibition is most effective in replicating cells and is due to impaired DNA damage repair. We also show that radiosensitization is still effective under hypoxia, suggesting that these inhibitors may help overcome hypoxia-induced radioresistance. In addition, we describe for the first time ART899 and characterize it as a potent and specific Polθ inhibitor with improved metabolic stability. In vivo, the combination of Polθ inhibition using ART899 with fractionated radiation is well tolerated and results in a significant reduction in tumor growth compared with radiation alone.These results pave the way for future clinical trials of Polθ inhibitors in combination with radiotherapy.CONCLUSIONSThese results pave the way for future clinical trials of Polθ inhibitors in combination with radiotherapy. |
| Author | Stockley, Martin L Higgins, Geoff S Ranzani, Marco Cerutti, Aurora Hammond, Ester M Grinkevich, Vera Millar, Val Ebner, Daniel Machado, Nicole Boursier, Marie Majithiya, Jayesh B Smith, Graeme C M Prevo, Remko Grande, Diego Galbiati, Alessandro Puliyadi, Rathi Cicconi, Alessandro Robinson, Helen M R Boulton, Simon J Heald, Robert A Rodriguez-Berriguete, Gonzalo Piscitello, Desiree Bolland, Hannah R Rajendra, Eeson |
| Author_xml | – sequence: 1 givenname: Gonzalo orcidid: 0000-0003-1613-0291 surname: Rodriguez-Berriguete fullname: Rodriguez-Berriguete, Gonzalo organization: Department of Oncology, University of Oxford, Oxford, United Kingdom – sequence: 2 givenname: Marco orcidid: 0000-0003-4253-3617 surname: Ranzani fullname: Ranzani, Marco organization: Artios Pharma, Babraham Research Campus, Cambridge, United Kingdom – sequence: 3 givenname: Remko orcidid: 0000-0001-5196-0552 surname: Prevo fullname: Prevo, Remko organization: Department of Oncology, University of Oxford, Oxford, United Kingdom – sequence: 4 givenname: Rathi orcidid: 0000-0002-7073-0725 surname: Puliyadi fullname: Puliyadi, Rathi organization: Department of Oncology, University of Oxford, Oxford, United Kingdom – sequence: 5 givenname: Nicole orcidid: 0000-0002-8168-3493 surname: Machado fullname: Machado, Nicole organization: Department of Oncology, University of Oxford, Oxford, United Kingdom – sequence: 6 givenname: Hannah R orcidid: 0000-0003-3740-1046 surname: Bolland fullname: Bolland, Hannah R organization: Department of Oncology, University of Oxford, Oxford, United Kingdom – sequence: 7 givenname: Val orcidid: 0000-0002-5642-019X surname: Millar fullname: Millar, Val organization: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom – sequence: 8 givenname: Daniel orcidid: 0000-0002-6495-7026 surname: Ebner fullname: Ebner, Daniel organization: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom – sequence: 9 givenname: Marie orcidid: 0000-0003-1899-7323 surname: Boursier fullname: Boursier, Marie organization: Artios Pharma, Babraham Research Campus, Cambridge, United Kingdom – sequence: 10 givenname: Aurora orcidid: 0000-0001-6385-3308 surname: Cerutti fullname: Cerutti, Aurora organization: Artios Pharma, Babraham Research Campus, Cambridge, United Kingdom – sequence: 11 givenname: Alessandro orcidid: 0000-0001-8248-3568 surname: Cicconi fullname: Cicconi, Alessandro organization: Artios Pharma, Babraham Research Campus, Cambridge, United Kingdom – sequence: 12 givenname: Alessandro orcidid: 0000-0002-8795-7934 surname: Galbiati fullname: Galbiati, Alessandro organization: Artios Pharma, Babraham Research Campus, Cambridge, United Kingdom – sequence: 13 givenname: Diego orcidid: 0000-0001-6770-9274 surname: Grande fullname: Grande, Diego organization: Artios Pharma, Babraham Research Campus, Cambridge, United Kingdom – sequence: 14 givenname: Vera orcidid: 0000-0001-7778-8826 surname: Grinkevich fullname: Grinkevich, Vera organization: Artios Pharma, Babraham Research Campus, Cambridge, United Kingdom – sequence: 15 givenname: Jayesh B orcidid: 0000-0003-2944-4871 surname: Majithiya fullname: Majithiya, Jayesh B organization: Artios Pharma, Babraham Research Campus, Cambridge, United Kingdom – sequence: 16 givenname: Desiree orcidid: 0000-0002-2510-4717 surname: Piscitello fullname: Piscitello, Desiree organization: Artios Pharma, Babraham Research Campus, Cambridge, United Kingdom – sequence: 17 givenname: Eeson orcidid: 0000-0002-5301-054X surname: Rajendra fullname: Rajendra, Eeson organization: Artios Pharma, Babraham Research Campus, Cambridge, United Kingdom – sequence: 18 givenname: Martin L orcidid: 0000-0002-3669-2948 surname: Stockley fullname: Stockley, Martin L organization: Artios Pharma, Babraham Research Campus, Cambridge, United Kingdom – sequence: 19 givenname: Simon J orcidid: 0000-0002-1125-8977 surname: Boulton fullname: Boulton, Simon J organization: The Francis Crick Institute, London, United Kingdom – sequence: 20 givenname: Ester M orcidid: 0000-0002-2335-3146 surname: Hammond fullname: Hammond, Ester M organization: Department of Oncology, University of Oxford, Oxford, United Kingdom – sequence: 21 givenname: Robert A orcidid: 0000-0003-3425-7130 surname: Heald fullname: Heald, Robert A organization: Artios Pharma, Babraham Research Campus, Cambridge, United Kingdom – sequence: 22 givenname: Graeme C M orcidid: 0000-0001-8320-4057 surname: Smith fullname: Smith, Graeme C M organization: Artios Pharma, Babraham Research Campus, Cambridge, United Kingdom – sequence: 23 givenname: Helen M R orcidid: 0000-0003-0414-0740 surname: Robinson fullname: Robinson, Helen M R organization: Artios Pharma, Babraham Research Campus, Cambridge, United Kingdom – sequence: 24 givenname: Geoff S orcidid: 0000-0003-3072-909X surname: Higgins fullname: Higgins, Geoff S organization: Department of Oncology, University of Oxford, Oxford, United Kingdom |
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| SubjectTerms | Cell Line, Tumor Humans Neoplasms - drug therapy Neoplasms - genetics Neoplasms - radiotherapy |
| Title | Small-Molecule Polθ Inhibitors Provide Safe and Effective Tumor Radiosensitization in Preclinical Models |
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