A1 Refereed original research article in a scientific journal
ALDH1A1-related stemness in high-grade serous ovarian cancer is a negative prognostic indicator but potentially targetable by EGFR/mTOR-PI3K/aurora kinase inhibitors
Authors: Katja Kaipio, Ping Chen, Pia Roering, Kaisa Huhtinen, Piia Mikkonen, Päivi Östling, Laura Lehtinen, Naziha Mansuri, Taina Korpela, Swapnil Potdar, Johanna Hynninen, Annika Auranen, Seija Grénman, Krister Wennerberg, Sampsa Hautaniemi, Olli Carpén
Publisher: Wiley
Publication year: 2020
Journal: Journal of Pathology
Journal name in source: The Journal of pathology
Journal acronym: J Pathol
Volume: 250
Issue: 2
First page : 159
Last page: 169
Number of pages: 11
ISSN: 0022-3417
eISSN: 1096-9896
DOI: https://doi.org/10.1002/path.5356
Web address : https://onlinelibrary.wiley.com/doi/10.1002/path.5356
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/43294853
Poor chemotherapy response remains a major treatment challenge for high-grade serous ovarian cancer. Cancer stem cells are the major contributors to relapse and treatment failure as they can survive conventional therapy. Our objectives were to characterise stemness features in primary patient derived cell lines, correlate stemness markers with clinical outcome, and test the response of our cells to both conventional and exploratory drugs. Tissue and ascites samples, treatment-naïve and/or after neoadjuvant chemotherapy, were prospectively collected. Primary cancer cells, cultured under conditions favouring either adherent or spheroid growth, were tested for stemness markers; the same markers were analysed in tissue and correlated with chemotherapy response and survival. Drug sensitivity and resistance testing was performed with 306 oncology compounds. Spheroid growth-condition HGSC cells showed increased stemness marker expression (including ALDH1A1) as compared to adherent growth-condition cells, and increased resistance to platinum and taxane. A set of eight stemness markers separated treatment-naïve tumours into two clusters and identified a distinct subgroup of HGSC with enriched stemness features. Expression of ALDH1A1, but not most other stemness markers, was increased after neoadjuvant chemotherapy and its expression in treatment-naïve tumours correlated with chemoresistance and reduced survival. In DSRT, five compounds, including two PI3K-mTOR inhibitors, demonstrated significant activity in both cell culture conditions. Thirteen compounds, including EGFR, PI3K-mTOR and aurora kinase inhibitors, were more toxic to spheroid cells than adherent cells. Our results identify stemness markers in HGSC that are associated with a decreased response to conventional chemotherapy and reduced survival if expressed by treatment-naïve tumours. EGFR, mTOR-PI3K and aurora kinase inhibitors are candidates for targeting this cell population.
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