PARP1 Inhibitor Combined With Oxaliplatin Efficiently Suppresses Oxaliplatin Resistance in Gastric Cancer-Derived Organoids via Homologous Recombination and the Base Excision Repair Pathway.

Axel Behrens,Zhenran Hu,Huafu Li,Leping Yan,Wei Chen,Ian Evans,Yulong He,Changhua Zhang,E. Josue Ruiz,Linxiang Lan,Wenhui Wu,Chunming Wang,Rui L. Reis,Zhijun Zhou,Joaquim M. Oliveira

doi:10.3389/fcell.2021.719192

Abstract

Oxaliplatin (OXA) resistance in the treatment of different types of cancer is an important and complex problem. The culture of tumor organoids derived from gastric cancer can help us to provide a deeper understanding of the underlying mechanisms that lead to OXA resistance. In this study, our purpose was to understand the mechanisms that lead to OXA resistance, and to provide survival benefits to patients with OXA through targeted combination therapies. Using sequence analysis of OXA-resistant and non-OXA-resistant organoids, we found that PARP1 is an important gene that mediates OXA resistance. Through the patients’ follow-up data, it was observed that the expression level of PARP1 was significantly correlated with OXA resistance. This was confirmed by genetic manipulation of PARP1 expression in OXA-resistant organoids used in subcutaneous tumor formation. Results further showed that PARP1 mediated OXA resistance by inhibiting the base excision repair pathway. OXA also inhibited homologous recombination by CDK1 activity and importantly made cancers with normal BRCA1 function sensitive to PARP inhibition. As a result, combination of OXA and Olaparib (PARP-1/2/3 inhibitor), inhibited in vivo and in vitro OXA resistant organoid growth and viability.

Highlights

RESULTSCurrently, the standard treatment for gastric cancer is surgical resection
Through immunohistochemistry and recurrence status of patients after adjuvant chemotherapy, we found that PARP1 was highly expressed in the tumors of patients who relapsed after adjuvant chemotherapy (Figures 9A–C)
Our study found that PARP1 inhibitors in combination with OXA have a powerful anti-tumor effect in gastric cancer patients without BRCA1 mutations

Summary

Introduction

The opportunity for surgery is often lost as the majority of cases are diagnosed at an advanced stage (Yuan et al, 2020). Alternative therapies such as radiotherapy and chemotherapy can be considered yet are often ineffective. In order to advance in the treatment of gastric cancer, there is an urgent need to gain a better understanding of the mechanisms of chemoresistance. This is necessary to provide a more “personalized” treatment to patients and to develop new strategies to overcome chemotherapy resistance

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Conclusion