Genetic mutations have been widely recognized as a primary mechanism of acquired drug resistance in ovarian cancer. However, a wide range of non-genetic mechanisms can also contribute to therapeutic evasion and cancer relapse. We have recently reported that selective mRNA translation leads to resistance to ribosome-targeting therapy by promoting the expression of proteins beneficial for cancer cell survival1. We herein hypothesized that mRNA translational reprogramming is a critical adaptative mechanism driving drug resistance in high grade serous ovarian cancer (HGSOC).
To investigate alterations in translational profiles, we performed polysome profiling analysis in a HGSOC cell line model including OVCAR8 cells made sensitive to the standard of care poly-ADP ribose polymerase inhibitors (PARPi) and chemotherapy by knocking out RAD51C and a clonal RARPi -resistant cell line. The data analysis using Anota2Seq method identified significant changes in subsets of translated mRNA of the resistant cells compared to the sensitive control. Moreover, the alterations observed in translated mRNA were mirrored by corresponding changes in matched cytoplasmic mRNA, indicating that changes in mRNA translation were linked to variations in transcription and/or mRNA stability. The enrichment analysis showed downregulation of biological processes involved “E2F targets”, “MYC targets”, “oxidative phosphorylation”, “apoptosis” and “interferon alpha response” which corresponded to reduced proliferative and metabolic states and immunogenicity observed in the resistant cells. We also identified enrichment of translated mRNAs involved in epithelial-mesenchymal-transition, supporting the invasive phenotypic changes associated with drug resistance. We further showed the altered mRNA translational profiles correlated with the proteomic profiles. These results thus support mRNA translational reprogramming mediates PARPi resistance in HGSOC. We will further analyze the adaptive translatomic and proteomic changes upon PARPi treatment in our unique set of matched sensitive and resistant HGSOC cell lines to provide more mechanistic insights to therapy resistance in HGSOC.