Subcutaneous mouse tumour models are widely used for the screening of novel antitumour treatments, although these models are poor surrogate models of human cancers.
We compared the antitumour efficacy of the combination of ionising radiation (IR) with two DNA damage response inhibitors, the PARP inhibitor olaparib and the ATR inhibitor AZD6738 (ceralasertib), in subcutaneous versus orthotopic cancer models.
Olaparib delayed the growth of irradiated Lewis lung carcinoma (LL2) subcutaneous tumours, in agreement with previous reports in human cell lines. However, the olaparib plus IR combination showed a very narrow therapeutic window against LL2 lung orthotopic tumours, with nearly no additional antitumour effect compared with that of IR alone, and tolerability issues emerged at high doses. The addition of AZD6738 greatly enhanced the efficacy of the olaparib plus IR combination treatment against subcutaneous but not orthotopic LL2 tumours. Moreover, olaparib plus AZD6738 administration concomitant with IR even worsened the response to radiation of head and neck orthotopic tumours and induced mucositis.
These major differences in the responses to treatments between subcutaneous and orthotopic models highlight the importance of using more pathologically relevant models, such as syngeneic orthotopic models, to determine the most appropriate therapeutic approaches for translation to the clinic.
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We thank V. Rouffiac, the Imaging and Cytometry Platform UMS 23/3655 and the PFEP animal facility (Gustave Roussy Cancer Campus). We thank M. Dos Santos and F. Milliat (IRSN, Fontenay-aux-Roses, France) for CT imaging.
Ethics approval and consent to participate
Animal procedures were performed according to protocols approved by the Ethics Committee CEEA26 (project no. 2015‐016‐613, EU directive 2010/63/EU). Female C57BL/6 mice were housed in the Gustave Roussy animal facility (animal care licence no. D94-076-11).
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The data that support the findings of this study are available from the corresponding authors upon reasonable request.
Mark J. O’Connor is an employee and shareholder of AstraZeneca.
This study was supported by a research grant from AstraZeneca to E. Deutsch.
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Tran Chau, V., Liu, W., Gerbé de Thoré, M. et al. Differential therapeutic effects of PARP and ATR inhibition combined with radiotherapy in the treatment of subcutaneous versus orthotopic lung tumour models. Br J Cancer (2020). https://doi.org/10.1038/s41416-020-0931-6