Precision Medicine in High-Grade Serous Ovarian Cancer - Targeted Therapies and the Challenge of Chemoresistance

Sep 24, 2026

High-grade serous ovarian cancer (HGSOC) carries a poor prognosis driven by its aggressive biology, late diagnosis, and the high mortality associated with chemoresistance. Even after initial response, disease recurrence occurs in roughly 80% of cases and is frequently resistant to carboplatin, limiting durable benefit. Novel targeted therapies have begun to reshape treatment, yet molecular diversity and acquired resistance mechanisms continue to restrict overall survival gains. The review evaluates approved targeted approaches and emerging trial targets, emphasizing precision medicine through risk prediction and patient selection.

LanguageEnglish

CategoryHealthcare

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Pages37

Reading Time1 h 33 min

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Abstract

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1. Introduction

Figure 1. Mechanisms of platinum resistance in ovarian cancer

Review Precision Medicine in High-Grade Serous Ovarian Cancer: Targeted Therapies and the Challenge of Chemoresistance Sara Polajžer and Katarina ˇCerne * Academic Editor: Sanjay K. Srivastava Received: 9 January 2025 Revised: 22 February 2025 Accepted: 8 March 2025 Published: 12 March 2025 Citation: Polajžer, S.; ˇCerne, K. Precision Medicine in High-Grade Serous Ovarian Cancer: Targeted Therapies and the Challenge of Chemoresistance. Int. J. Mol. Sci. 2025, 26, 2545. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms26062545 Copyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://creativecommons.org/](https://creativecommons.org/)[ ](https://creativecommons.org/)[licenses/by/4.0/](licenses/by/4.0/)) . Institute of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Korytkova 2, SI-1000 Ljubljana, Slovenia; [sara.polajzer@mf.uni-lj.si](sara.polajzer@mf.uni-lj.si) * Correspondence: [katarina.cerne@mf.uni-lj.si](katarina.cerne@mf.uni-lj.si) Abstract: The poor prognosis for high-grade serous ovarian cancer (HGSOC), the dominant subtype of ovarian cancer, reflects its aggressive nature, late diagnosis, and the highest mortality rate among all gynaecologic cancers. Apart from late diagnosis, the main reason for the poor prognosis and its unsuccessful treatment is primarily the emergence of chemoresistance to carboplatin. Although there is a good response to primary treatment, the disease recurs in 80% of cases, at which point it is largely resistant to carboplatin. The introduction of novel targeted therapies in the second decade of the 21st century has begun to transform the treatment of HGSOC, although their impact on overall survival remains unsatisfactory. Targeting the specific pathways known to be abnormally activated in HGSOC is especially difficult due to the molecular diversity of its subtypes. Moreover, a range of molecular changes are associated with acquired chemoresistance, e.g., reversion of BRCA1 and BRCA2 germline alleles. In this review, we examine the advantages and disadvantages of approved targeted therapies, including bevacizumab, PARP inhibitors (PARPis), and treatments targeting cells with neurotrophic tyrosine receptor kinase (NTRK), B-rapidly accelerated fibrosarcoma (BRAF), and rearranged during transfection (RET) gene alterations, as well as antibody–drug conjugates. Additionally, we explore promising new targets under investigation in ongoing clinical trials, such as immune checkpoint inhibitors, anti-angiogenic agents, phosphatidylinositol-3-kinase (PI3K) inhibitors, Wee1 kinase inhibitors, and ataxia telangiectasia and Rad3-related protein (ATR) inhibitors for platinum-resistant disease. Despite the development of new targeted therapies, carboplatin remains the fundamental medicine in HGSOC therapy. The correct choice of treatment strategy for better survival of patients with advanced HGSOC should therefore include a prediction of patients’ risks of developing chemoresistance to platinum-based chemotherapy. Moreover, effective targeted therapy requires the selection of patients who are likely to derive clinical benefit while minimizing potential adverse effects, underscoring the essence of precision medicine. Keywords: high-grade serous ovarian cancer; chemoresistance; ovarian cancer; targeted therapies; predictive biomarker 1. Introduction Ovarian cancer (OC), in spite of its infrequent incidence, is the most lethal malignancy of the female reproductive system [1] . According to the GLOBOCAN database (Global Cancer Observatory established by IARC, WHO, Lyon, France), a total of 324,603 new cases and 206,956 new deaths were recorded globally in 2022 [2] . The poor prognosis of OC is primarily due to its late detection, with over two-thirds of patient

FAQs

Why is the prognosis poor in high-grade serous ovarian cancer (HGSOC)?

The review links poor prognosis to aggressive disease, late diagnosis, and a high mortality burden. A central driver is the emergence of chemoresistance to carboplatin.

What role does chemoresistance to carboplatin play in recurrence?

Although HGSOC often responds to primary treatment, the disease recurs in about 80% of cases. At recurrence, it is largely resistant to carboplatin, undermining long-term control.

Which targeted therapies and mechanisms does the review focus on?

The review discusses approved targeted therapies such as bevacizumab and PARP inhibitors, and therapies targeting NTRK, BRAF, and RET alterations, as well as antibody–drug conjugates. It also highlights investigational targets in clinical trials, including immune checkpoint inhibitors, PI3K inhibitors, Wee1 kinase inhibitors, and ATR inhibitors for platinum-resistant disease.

Sep 24, 2026

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