ALDH1A1-related stemness in high-grade serous ovarian cancer is a negative prognostic indicator but potentially targetable by EGFR/mTOR-PI3K/aurora kinase inhibitors
Open accessAbstract
Poor chemotherapy response remains a major treatment challenge for high‐grade serous ovarian cancer (HGSC). 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‐naive 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 aldehyde dehydrogenase isoform I; ALDH1A1) as compared with adherent growth condition cells, and increased resistance to platinum and taxane. A set of eight stemness markers separated treatment‐naive 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‐naive tumours correlated with chemoresistance and reduced survival. In drug sensitivity and resistance testing, 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‐naive tumours. EGFR, mTOR‐PI3K and aurora kinase inhibitors are candidates for targeting this cell population. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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CIP2A is linked to stemness traits in patient-derived high-grade serous cancer cells.
“CIP2A was recently also shown in cell culture to protect OvCa cells from Cisplatin-induced apoptosis (10), and to associate with stemness features in patient-derived high grade serous cancer (HGSC) cells (11).”
From Ovarian Cancers with Low CIP2A Tumor Expression Constitute an APR-246–Sensitive Disease Subtype (2022) · cites this paper as [11]
APR-246 plus NF-kB inhibition was also effective in patient-derived ovarian cancer cell line OC002.
“Finally, the combined action of APR-246 and NF-kB inhibition was validated in patient-derived OvCa cell line OC002 derived from a patient with disseminated disease (Fig. 4I)(11).”
From Ovarian Cancers with Low CIP2A Tumor Expression Constitute an APR-246–Sensitive Disease Subtype (2022) · cites this paper as [11]
The drug-sensitivity testing section reports results for patient-derived lines M019i, M068i, and M022i, but does not report an APR-246/NF-κB inhibitor combination in OC002. Searches for APR-246, OC002, and NF-κB inhibition found no passage describing the claimed validation; the NF-κB mention is in a reference to a different study (References; page unavailable). (LLM, conf=0.76)
Experimental — accuracy not yet measuredCIP2A associates with stemness features in patient-derived high grade serous cancer cells.
“and to associate with stemness features in patient-derived high grade serous cancer (HGSC) cells (11).”
From Ovarian cancers with low CIP2A tumor expression constitute an APR-246 sensitive disease subtype (2021) · cites this paper as [11]
The combined action of APR-246 and NF-kB inhibition was validated in patient-derived OvCa cell line OC002 derived from a patient with disseminated disease.
“Finally, the combined action of APR-246 and NF-kB inhibition was validated in patient-derived OvCa cell line OC002 derived from a patient with disseminated disease (Fig.4I)(11).”
From Ovarian cancers with low CIP2A tumor expression constitute an APR-246 sensitive disease subtype (2021) · cites this paper as [11]
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Ovarian Cancers with Low CIP2A Tumor Expression Constitute an APR-246–Sensitive Disease Subtype
Cvrljevic, A. N., Butt, U., Huhtinen, K., Grönroos, T. J., Böckelman, C., Lassus, H., Butzow, R., Haglund, C., Kaipio, K., Arsiola, T., et al. (2022) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-21-0622 · Cited by 5 · see citing works
Self-citationOvarian cancers with low CIP2A tumor expression constitute an APR-246 sensitive disease subtype
Cvrljevic, A. N., Butt, U., Huhtinen, K., Grönroos, T. J., Böckelman, C., Lassus, H., Kaipio, K., Arsiola, T., Laajala, T. D., Connolly, D. C., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.03.31.437804 · Cited by 5 · see citing works
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- Authors
- Kaipio, K., Chen, P., Roering, P., Huhtinen, K., Mikkonen, P., Östling, P., Lehtinen, L., Mansuri, N., Korpela, T., Potdar, S., Hynninen, J., Auranen, A., Grénman, S., Wennerberg, K., Hautaniemi, S., & Carpén, O.
- Affiliations
- University of Turku (FI)
- Karolinska Institutet (SE)
- University of Helsinki (FI)
- Tampere University Hospital (FI)
- University of Copenhagen (DK)
- Corresponding author
- Kaipio, Katja
- ORCID
- Venue
- The Journal of Pathology
- Publisher
- Wiley
- Published
- 2019-12-03
- Volume
- 250
- Issue
- 2
- Pages
- 159-169
- ISSN
- 0022-3417 (ISSN-L)
- 1096-9896
- OpenAlex
- W2979766702
- Semantic Scholar
- fbf0a1b9dee4b854084fc899a7a0ef444f2d6e0d
- Cited by
- 54
- References
- 55
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 11 · 2023: 7 · 2022: 12 · 2021: 11 · 2020: 3 · 2019: 1
- FWCI
- 6.70
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- The Journal of Pathology (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- Työväentutkimus Vuosikirja (submittedVersion)
- UTUPub (University of Turku) (submittedVersion)
- Funders
- Academy of Finland (292606)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- high-grade serous ovarian cancer, cancer stem cells, ALDH1A1, stem cell markers, chemoresistance, neoadjuvant chemotherapy, spheroid growth, drug sensitivity, drug resistance, PI3K/mTOR inhibitors, EGFR inhibitors, Aurora kinase inhibitors, prognostic factors, survival
- MeSH terms
- Aldehyde Dehydrogenase 1 Family, Antineoplastic Agents, Drug Screening Assays, Antitumor, Female, Humans, Ovarian Neoplasms, Prognosis, Tumor Cells, Cultured, Biomarkers, Tumor, Neoplastic Stem Cells, Chemotherapy, Adjuvant, Cystadenocarcinoma, Serous, Spheroids, Cellular, Drug Resistance, Neoplasm, Retinal Dehydrogenase, TOR Serine-Threonine Kinases, Molecular Targeted Therapy, Neoplasm Grading, Aurora Kinases, ErbB Receptors
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