Chalk, Avigayil;
(2021)
Combining ATR inhibition with topoisomerase I inhibitors for the treatment of colorectal cancer.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Metastatic colorectal cancers are commonly treated with irinotecan, a topoisomerase 1 (TOP1) inhibitor. TOP1 inhibition results in the formation of TOP1-DNA cleavage complexes, which induce replication stress, and lead to activation of the Ataxia Telangiectasia and Rad-3 related (ATR) signalling pathway. Activation of ATR leads to cell cycle arrest and DNA repair, reducing the cytotoxicity of TOP1 inhibition. Using a panel of colorectal cancer (CRC) cell lines and patient derived organoids (PDOs), a synergistic interaction was identified between SN38 (active irinotecan metabolite) and VX-970 (ATR inhibitor). Treating CRC cell lines and PDOs with a combination of TOP1 and ATR inhibition resulted in increased ƔH2AX accumulation and the activation of double strand break (DSB) repair kinases, DNA-PK and ATM. Increased DNA DSBs and the formation of micronuclei in combination treated cells, further demonstrated the elevated levels of DNA damage. Colocalisation of cGAS with micronuclei was detected in combination treated cells, suggesting increased DNA damage may result in immune activation. Trastuzumab deruxtecan (DS-8201a) is a novel HER2 targeting antibody drug conjugate (ADC), carrying a potent TOP1 inhibitor (Dxd) warhead. Previous studies have reported minimal sensitivity of HER2-low expressing CRCs to DS-8201a therapy. In this study, several HER2-low CRC cell lines and PDOs were sensitised to DS-8201a by ATR inhibition (VX-970 and AZD6738). Loss of replication arrest and increased DNA-damage were identified as the mechanisms for the synergy observed. ATR inhibition was also explored as a possible mechanism to overcome irinotecan resistance. However, neither ATR inhibition combined with SN38, or ATR inhibition combined with DS-8201a was effective at reducing survival in two SN38 resistant cell lines. Understanding the interaction between TOP1 and ATR inhibition will better inform the treatment of CRC.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Combining ATR inhibition with topoisomerase I inhibitors for the treatment of colorectal cancer |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10140956 |
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