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.