ALDH1A1-related stemness in high-grade serous ovarian cancer is a negative prognostic indicator but potentially targetable by EGFR/mTOR-PI3K/aurora kinase inhibitors
Journal of Pathology Oct 18, 2019
Kaipio K, Chen P, Roering P, et al. - Tissue and ascites samples, treatment-naïve and/or following neoadjuvant chemotherapy, were prospectively obtained in order to characterize stemness characteristics in primary patient-derived cell lines, associate stemness markers with clinical outcome, and examine the response of our cells to both conventional and exploratory drugs. In comparison with adherent growth-condition cells, progressed stemness marker expression (including aldehyde dehydrogenase isoform I [ALDH1A1]) and enhanced resistance to platinum and taxane were exhibited by spheroid growth-condition High grade serous ovarian carcinoma (HGSC) cells. A set of eight stemness markers isolated treatment-naïve tumors into two clusters and recognized a different subgroup of HGSC with increased stemness features. Expression of ALDH1A1, however, not most other stemness markers, was raised following neoadjuvant chemotherapy and its expression in treatment-naïve tumors related to chemoresistance and diminished survival. In drug sensitivity and resistance testing, five composites, comprising two PI3K-mTOR inhibitors, exhibited notable activity in both cell culture conditions. Thirteen compounds, comprising EGFR, PI3K-mTOR and aurora kinase inhibitors, were more toxic in nature to spheroid cells vs adherent cells. In conclusion, the results recognize that if expressed by treatment-naïve tumors, stemness markers in HGSC correlated with a reduced response to conventional chemotherapy and decreased survival. Moreover, for targeting this cell population, EGFR, mTOR-PI3K and aurora kinase inhibitors are nominees.
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