Using Patient-Derived Xenograft (PDX) Models as a 'Black Box' to Identify More Applicable Patients for ADP-Ribose Polymerase Inhibitor (PARPi) Treatment in Ovarian Cancer: Searching for Novel Molecular and Clinical Biomarkers and Performing a Prospective Preclinical Trial.

Abstract

Simple SummaryThe clinical application of PARPis in patients with ovarian cancer has unresolved issues, and whether PARPis can have a similar first-line efficacy to that of platinum-based chemotherapy is still undefined. This study used the PDX model to explore the above problems. We demonstrated that the PDX model can reflect PARPi efficacy more accurately than BRCA mutation, homologous recombination deficiency positivity, and platinum sensitivity. Moreover, the novel clinical and molecular biomarkers suggested that KRAS overexpression was associated with PARPi sensitivity. Additionally, ATK1 enrichment could lead to PARPi resistance, and CA125 less than 10 U/mL during chemotherapy can be a potential indicator for the therapeutic use of PARPi. Above all, PARPis cannot replace platinum-based chemotherapy as first-line treatment in our preclinical trial, indicating that chemotherapy-free tests in the unselected population are not recommended.(1) The accuracy of patient-derived xenografts (PDXs) in predicting ADP-ribose polymerase inhibitor (PARPi) efficacy in ovarian cancer was tested, novel biomarkers were investigated, and whether PARPis could replace platinum-based chemotherapy as a first-line therapy was explored. (2) PDXs were reconstructed for 40 patients with ovarian cancer, and niraparib, olaparib and paclitaxel, and carboplatin (TC) sensitivity tests were conducted. Whole exon sequencing and homologous recombination deficiency (HRD) scores were performed, and patient clinical information was collected. The molecular biomarkers were identified by reverse-transcription quantitative PCR and immunoblotting. (3) Niraparib and olaparib sensitivity were tested in 26 patients and showed high consistency. Approximately half of BRCA wild-type, HRD-negative, and platinum-resistant patients may benefit from PARPis. AKT1 enrichment indicated PARPi resistance; high KRAS expression indicated PARPi sensitivity. CA125 below 10 U/mL during chemotherapy has a sensitivity and specificity similar to platinum sensitivity in predicting PARPi efficacy. Niraparib and TC sensitivity tests were performed on 23 patients, and TC showed a better response in this preclinical trial. (4) PDX can indicate individualized PARPi efficacy. Decreased CA125 levels and KRAS and ATK1 expression levels may be novel biomarkers. The preclinical evidence does not support the implementation of PARPis as the first-line treatment in an unselected population.