University of Oulu

Murumägi, A., Ungureanu, D., Khan, S. et al. Drug response profiles in patient-derived cancer cells across histological subtypes of ovarian cancer: real-time therapy tailoring for a patient with low-grade serous carcinoma. Br J Cancer 128, 678–690 (2023). https://doi.org/10.1038/s41416-022-02067-z

Drug response profiles in patient-derived cancer cells across histological subtypes of ovarian cancer : real-time therapy tailoring for a patient with low-grade serous carcinoma

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Author: Murumägi, Astrid1; Ungureanu, Daniela2,3; Khan, Suleiman1,4;
Organizations: 1Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
2Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
3Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
4Helsinki Institute for Information Technology (HIIT), Department of Computer Science, Aalto University, Espoo, Finland
5Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden
6Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
7Tartu University Hospital, Tartu, Estonia
8Department of Clinical Genomic Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
9Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
10iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, Finland
11Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
12Institute for Cancer Research, Department of Cancer Genetics, Oslo University Hospital, Oslo, Norway
13Centre for Biostatistics and Epidemiology (OCBE), Faculty of Medicine, University of Oslo, Oslo, Norway
14Science for Life Laboratory (SciLifeLab), Department of Oncology and Pathology, Karolinska Institutet, Solna, Sweden
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe20231103142871
Language: English
Published: Springer Nature, 2022
Publish Date: 2023-11-03
Description:

Abstract

Many efforts are underway to develop novel therapies against the aggressive high-grade serous ovarian cancers (HGSOCs), while our understanding of treatment options for low-grade (LGSOC) or mucinous (MUCOC) of ovarian malignancies is not developing as well. We describe here a functional precision oncology (fPO) strategy in epithelial ovarian cancers (EOC), which involves high-throughput drug testing of patient-derived ovarian cancer cells (PDCs) with a library of 526 oncology drugs, combined with genomic and transcriptomic profiling. HGSOC, LGSOC and MUCOC PDCs had statistically different overall drug response profiles, with LGSOCs responding better to targeted inhibitors than HGSOCs. We identified several subtype-specific drug responses, such as LGSOC PDCs showing high sensitivity to MDM2, ERBB2/EGFR inhibitors, MUCOC PDCs to MEK inhibitors, whereas HGSOCs showed strongest effects with CHK1 inhibitors and SMAC mimetics. We also explored several drug combinations and found that the dual inhibition of MEK and SHP2 was synergistic in MAPK-driven EOCs. We describe a clinical case study, where real-time fPO analysis of samples from a patient with metastatic, chemorefractory LGSOC with a CLU-NRG1 fusion guided clinical therapy selection. fPO-tailored therapy with afatinib, followed by trastuzumab and pertuzumab, successfully reduced tumour burden and blocked disease progression over a five-year period. In summary, fPO is a powerful approach for the identification of systematic drug response differences across EOC subtypes, as well as to highlight patient-specific drug regimens that could help to optimise therapies to individual patients in the future.

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Series: British journal of cancer
ISSN: 0007-0920
ISSN-E: 1532-1827
ISSN-L: 0007-0920
Volume: 128
Issue: 4
Pages: 678 - 690
DOI: 10.1038/s41416-022-02067-z
OADOI: https://oadoi.org/10.1038/s41416-022-02067-z
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Subjects:
Funding: This study was supported by grants from the Academy of Finland (grants 278741, 313267, 326238, 333583, 313267, 326238, and 344698), Academy of Finland Centre of Excellence for Translational Cancer Biology (grant 271845), Cancer Society of Finland (grants 140114, 160080, 170112), Sigrid Jusélius Foundation. OK was also supported by Vetenskaprådet, Knut and Alice Wallenberg Foundation, Swedish Foundation for Strategic Research and Vinnova. Open Access funding provided by University of Helsinki including Helsinki University Central Hospital.
Copyright information: © The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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