The role of patient-derived ovarian cancer organoids in the study of PARP inhibitors sensitivity and resistance: from genomic analysis to functional testing

Mengyu Tao,Xia Wu

doi:10.1186/s13046-021-02139-7

Abstract

Epithelial ovarian cancer (EOC) harbors distinct genetic features such as homologous recombination repair (HRR) deficiency, and therefore may respond to poly ADP-ribose polymerase inhibitors (PARPi). Over the past few years, PARPi have been added to the standard of care for EOC patients in both front-line and recurrent settings. Next-generation sequencing (NGS) genomic analysis provides key information, allowing for the prediction of PARPi response in patients who are PARPi naïve. However, there are indeed some limitations in NGS analyses. A subset of patients can benefit from PARPi, despite the failed detection of the predictive biomarkers such as BRCA1/2 mutations or HRR deficiency. Moreover, in the recurrent setting, the sequencing of initial tumor does not allow for the detection of reversions or secondary mutations restoring proficient HRR and thus leading to PARPi resistance. Therefore, it becomes crucial to better screen patients who will likely benefit from PARPi treatment, especially those with prior receipt of maintenance PARPi therapy. Recently, patient-derived organoids (PDOs) have been regarded as a reliable preclinical platform with clonal heterogeneity and genetic features of original tumors. PDOs are found feasible for functional testing and interrogation of biomarkers for predicting response to PARPi in EOC. Hence, we review the strengths and limitations of various predictive biomarkers and highlight the role of patient-derived ovarian cancer organoids as functional assays in the study of PARPi response. It was found that a combination of NGS and functional assays using PDOs could enhance the efficient screening of EOC patients suitable for PARPi, thus prolonging their survival time.

Highlights

Epithelial ovarian, tubal, or primary peritoneal cancer represents the most devastating gynecologic cancer
The high prevalence of homologous recombination deficiency (HRD) is only partly explained by single gene mutations because, apart from BRCA1/2, only a very small number of other causal mutations in homologous recombination repair (HRR) related genes have been identified, such as RAD51, Ataxia telangiectasia mutated (ATM), ATRand PALB2 [8]
A subset of patients can benefit from PARP inhibitors (PARPi), despite the failed detection of the predictive biomarkers such as BRCA1/2 mutations or HRD

Summary

Introduction

Epithelial ovarian, tubal, or primary peritoneal cancer (hereinafter referred to as EOC) represents the most devastating gynecologic cancer. 3D tumor models using freshly resected samples, such as solid tumors (localized or metastatic), spheroids (from fluid paracentesis) or circulating tumor cells (from blood) are used to assess the therapeutic effects of PARPi. It was shown in some studies that short-term cultured PDOs can directly or indirectly predict the PARPi sensitivity of individuals through drug susceptibility tests and DNA damage repair functional assays.

Results

Conclusion