Differential therapeutic effects of PARP and ATR inhibition combined with radiotherapy in the treatment of subcutaneous versus orthotopic lung tumour models

Vanessa Tran Chau,Winchygn Liu,Céline Clémenson,Lydia Meziani,Mark J. O’Connor,Michele Mondini,Marine Gerbé de Thoré,Eric Deutsch

doi:10.1038/s41416-020-0931-6

Abstract

BackgroundSubcutaneous mouse tumour models are widely used for the screening of novel antitumour treatments, although these models are poor surrogate models of human cancers.MethodsWe 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.ResultsOlaparib 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.ConclusionsThese 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.

Highlights

Subcutaneous mouse tumour models are widely used for the screening of novel antitumour treatments, these models are poor surrogate models of human cancers
Olaparib enhances the effect of ionising radiation (IR) against subcutaneous murine LL2-luc syngeneic tumours As observed in human cell lines,[14,34] IR induced a moderate and transient increase in PAR levels in vitro in the BRCA wild-type, murine LL2-luc luciferase-expressing Lewis lung carcinoma cell line (Fig. 1a)
Our results suggest that the efficacy of the olaparib plus IR combination in the orthotopic tumour model is limited by the toxicity induced by high doses of irradiation or olaparib

Summary

Introduction

Subcutaneous mouse tumour models are widely used for the screening of novel antitumour treatments, these models are poor surrogate models of human cancers. The addition of AZD6738 greatly enhanced the efficacy of the olaparib plus IR combination treatment against subcutaneous but not orthotopic LL2 tumours. One of its limitations lies in its toxicity to normal tissues that are close to the radiation field.[1] In addition, accumulating preclinical and clinical evidence indicates that the microenvironment and the immune system modulate the antitumour efficacy of cytotoxic treatments, such as RT.[2,3,4] the proper preclinical evaluation of novel therapeutic strategies that include RT should be performed with models recapitulating at best the ‘physiological' tumour environment, comprising the pertinent tumour stroma, an intact immune system and the presence of the appropriate surrounding healthy tissues. Preclinical data in tumours grafted orthotopically in immunocompetent hosts are sparse

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