High-grade serous ovarian cancer (HGSOC) is the most common and lethal subtype of ovarian cancer with a 5-year survival rate of only 49%. Patients initially respond favourably to the standard-of-care chemotherapy and poly-ADP ribose polymerase inhibitors (PARPi). However, relapse is common leading to incurable disease within 2-3 years. This makes the search for new therapies a critical unmet clinical need.
Our analysis of matched PARPi-sensitive and -resistant HGSOC cell lines identified altered translational activity with down-regulation of STK11 expression associated with drug resistance. STK11 is a tumour suppressor that regulates mRNA translation activity via its substrate AMPK. These findings link altered mRNA translation activity to therapeutic resistance in HGSOC. We thus propose that translational reprogramming promotes acquired resistance to PARPi and chemotherapy in HGSOC by driving the expression of proteins beneficial for cancer cell survival.
Analysis of the TCGA database show that 18% of samples have STK11 mutations/aberrant expression, of which 4.5% have deep deletion suggesting that STK11 deficiency is common in HGSOC. Moreover, STK11 mRNA levels are significantly reduced in ovarian tumours compared to adjacent normal tissues. To assess the functional role of STK11 in HGSOC, we have established OVCAR3 cell lines with biallelic or monoallelic STK11 deletion using CRISPR-Cas9 editing. We demonstrate that STK11 deficiency confers resistance to olaparib and cisplatin. Strikingly, STK11 deficiency sensitizes OVCAR3 cells to everolimus (a mTORC1 inhibitor) and metformin (a drug that activates AMPK by decreasing energy level), suggesting that therapies that target AMPK-mTORC1 signaling may be effective in this subtype of HGSOC. Moreover, we performed polysome profiling in our PARPi-sensitive and resistant cell line models to identify significantly over- and under-represented mRNA species in polysomal fractions (translatome) compared to cytoplasmic fractions (transcriptome). We have identified the mRNAs encoding proteins associated with embryo development were translationally upregulated. Future studies will focus on characterization of the functional impact of STK11 on mRNA translational activity.
Altogether, our research provides a new understanding of the biology of acquired resistance in ovarian cancer that will enable the development of new effective therapies for HGSOC patients with STK11 mutations.