Genomic, Transcriptomic, and Functional Alterations in DNA Damage Response Pathways as Putative Biomarkers of Chemotherapy Response in Ovarian Cancer

Abstract

Simple Summary Several chemotherapy drugs are approved for ovarian cancer treatment in the neo-adjuvant/adjuvant setting as well as following relapse. These include carboplatin, paclitaxel, doxorubicin, topotecan, PARP inhibitors (PARPi), and gemcitabine. However, except for PAPRi, there are no predictive biomarkers to guide the choice of drug. The majority of chemotherapeutic drugs function by inducing DNA damage or inhibiting its repair. However, the association of DNA damage repair (DDR) pathway alterations with therapy response remain unclear. In this study, using a panel of 14 ovarian cancer cell lines, 10 patient ascites-derived primary cultures and bioinformatic analysis of The Cancer Genome Atlas (TCGA) ovarian cancer dataset, we identified the role of genomic/transcriptomic and/or functional alterations in DDR pathways as determinants of therapy response. Abstract Defective DNA damage response (DDR) pathways are enabling characteristics of cancers that not only can be exploited to specifically target cancer cells but also can predict chemotherapy response. Defective Homologous Recombination Repair (HRR) function, e.g., due to BRCA1/2 loss, is a determinant of response to platinum agents and PARP inhibitors in ovarian cancers. Most chemotherapies function by either inducing DNA damage or impacting on its repair but are generally used in the clinic unselectively. The significance of HRR and other DDR pathways in determining response to several other chemotherapy drugs is not well understood. In this study, the genomic, transcriptomic and functional analysis of DDR pathways in a panel of 14 ovarian cancer cell lines identified that defects in DDR pathways could determine response to several chemotherapy drugs. Carboplatin, rucaparib, and topotecan sensitivity were associated with functional loss of HRR (validated in 10 patient-derived primary cultures) and mismatch repair. Two DDR gene expression clusters correlating with treatment response were identified, with PARP10 identified as a novel marker of platinum response, which was confirmed in The Cancer Genome Atlas (TCGA) ovarian cancer cohort. Reduced non-homologous end-joining function correlated with increased sensitivity to doxorubicin, while cells with high intrinsic oxidative stress showed sensitivity to gemcitabine. In this era of personalised medicine, molecular/functional characterisation of DDR pathways could guide chemotherapy choices in the clinic allowing specific targeting of ovarian cancers.