Abstract
Simple SummarySeveral 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.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.
Highlights
Ovarian cancer accounts for ~300,000 new cancer cases globally each year and is one of the leading causes of death among gynaecological cancers, with a mortality rate of ~185,000 deaths per year [1]
% survival given concentration of technical replicates of three independent values determined more sensitive to doxorubicin as seen by the difference in the mean in experiments. (C) HRR deficient (HRD) primary cultures were more sensitive to carboplatin and rucaparib while HRR competent (HRC) primary cultures were by Sulforhodamine B (SRB) assay, each data point represents a single patient-derived primary culture (D) %Non-Homologous End Joining (NHEJ) activity more sensitive to doxorubicin as seen by the difference in the mean in GI50 values determined measured by plasmid re-joining assay
Utilising a panel of cell lines with different histologic subtypes, we identified that high grade serous ovarian cancer (HGSOC) cell lines (Kuramochi, COV318, CAOV3, ES2, NIH-OVCAR3, UWB1.289, UWB1.289 + BRCA1, and COV362) were more sensitive to carboplatin, gemcitabine, topotecan and rucaparib, while the non-HGSOC cell lines (OAW42, A2780, CP70-B1, CP70-A2, IGROV1, and NUCOLL43) were more sensitive to doxorubicin and paclitaxel
Summary
Ovarian cancer accounts for ~300,000 new cancer cases globally each year and is one of the leading causes of death among gynaecological cancers, with a mortality rate of ~185,000 deaths per year [1]. Combination platinum and paclitaxel chemotherapy in conjunction with cytoreductive surgery remain the cornerstone of first-line treatment for ovarian cancers, the majority of which present at an advanced stage. Whilst the majority of HGSOCs respond to platinum-based therapy with an initial response rate of ~60%, non-HGSOC subtypes (clear cell, mucinous and low grade serous) are less responsive [3,4]. HGSOC, the five-year overall survival remains poor (~45%), with the majority of women experiencing disease recurrence and the development of platinum resistance [5]. Non-platinum chemotherapy approved for second and third-line treatments and used in the resistant settings includes paclitaxel, liposomal doxorubicin, topotecan given alone or in combination with bevacizumab [3,9]. With the exception of stratification for PARPi therapy using BRCA mutation status, treatment strategies are not guided by molecular or functional features of individual cancers, making the prediction of response, and the selection of an appropriate agent, challenging
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