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

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.