6 days ago
Fact or Fiction: Ovarian Cancer and Drug Resistance
In ovarian cancer, the emergence of drug resistance has been shown to limit the durability of therapeutic treatment benefit and contribute substantially to ovarian cancer's high mortality rate. Factors such as treatment-free intervals and tumor microevolution may allow for re-sensitization to platinum agents in select patients. In addition to tumor biology, the tumor microenvironment plays a pivotal role in therapeutic resistance. Targeted therapies, once heralded as a solution to chemotherapy resistance, have been shown to face similar obstacles. Drug resistance in ovarian cancer management is an ongoing field of study as clinicians look to limit its impact improve outcomes.
Platinum resistance in ovarian cancer is not always permanent. While many patients relapse with tumors less responsive to platinum-based chemotherapy, resistance can be dynamic. Mechanisms such as epigenetic alterations, modulation of DNA damage response, and temporary activation of drug efflux pumps may contribute to reversible resistance. Importantly, a subset of patients initially labeled as platinum-resistant may benefit from platinum rechallenge after a treatment-free interval, particularly if newer maintenance strategies or resensitizing agents are used. This has led to the concept of a "platinum-free interval" to help guide re-treatment. Understanding these nuances is crucial for tailoring treatment strategies and optimizing outcomes.
Learn more about medications used in ovarian cancer.
While HRD — often due to BRCA1/2 mutations — initially predicts strong sensitivity to DNA-damaging therapies like platinum agents and PARP inhibitors, resistance commonly emerges over time. A key mechanism is the restoration of homologous recombination through secondary or "reversion" mutations in HR pathway genes. These mutations enable tumor cells to resume high-fidelity DNA repair, diminishing the cytotoxic effects of therapy. Additionally, tumors may activate compensatory pathways such as non-homologous end joining or increase drug efflux activity. This resistance may not be detectable at diagnosis and can evolve under therapeutic pressure. Consequently, current research emphasizes longitudinal molecular monitoring to capture evolving resistance mechanisms. Clinically, this underscores the need for re-biopsy or circulating tumor DNA analysis to reassess HR status in recurrent disease, which may influence therapy selection.
Learn more about the importance of biopsy in ovarian cancer.
Tumor heterogeneity — both genetic and phenotypic — plays a central role in drug resistance and further complications treatment outcomes. Ovarian tumors often consist of diverse subclonal populations, some of which may possess innate resistance traits. Within a single ovarian tumor, multiple subclonal populations may coexist, each with distinct characteristics and sensitivity profiles. When systemic therapy is applied, sensitive clones are eliminated, but resistant ones may persist and expand. Single-cell and spatial transcriptomics studies have mapped how this clonal evolution occurs, revealing that treatment can select for resistant subpopulations not evident at baseline. Heterogeneity also affects the tumor microenvironment and immune response, further complicating therapeutic strategies. Clinically, this variability can manifest as mixed responses, where some lesions regress while others progress. Addressing heterogeneity remains a major challenge and has sparked interest in combination therapies and adaptive trial designs. Personalized treatment strategies based on real-time tumor profiling are likely to improve outcomes by accounting for this complexity.
Learn more about ovarian cancer guidelines.
Targeted therapies are susceptible to various resistance mechanisms, many of which overlap with those seen in chemotherapy. For example, resistance to PARP inhibitors, widely used in HRD-positive ovarian cancers, can arise from secondary mutations restoring DNA repair function or through enhanced drug efflux. Similarly, resistance to angiogenesis inhibitors may develop via upregulation of alternative pro-angiogenic pathways or changes in tumor vasculature that circumvent the need for VEGF signaling. Resistance is further complicated by factors such as epigenetic reprogramming and altered cell signaling networks. These findings have led to interest in combining targeted agents with immune checkpoint inhibitors, DNA repair modulators, or epigenetic therapies to overcome resistance. Future success with targeted therapy will likely depend on combination approaches informed by tumor genomics and adaptive resistance profiling.
Learn more about risk assessment and genetic counseling in ovarian cancer.
The tumor microenvironment (TME) is a key contributor to drug resistance in ovarian cancer. Immune cells such as regulatory T cells and tumor-associated macrophages (TAMs) create an immunosuppressive milieu that hinders effective therapy. Additionally, fibroblasts and extracellular matrix components can form physical barriers that limit drug penetration. Cytokines and growth factors secreted within the TME also modulate signaling pathways in tumor cells, promoting survival and resistance. Studies have shown that high TAM density is associated with poor response to both chemotherapy and immunotherapy, and interventions targeting the TME may help reverse resistance. This includes strategies like macrophage reprogramming, TME remodeling agents, and stromal-targeting therapies. Incorporating TME characteristics into clinical decision-making may help guide therapeutic combinations and predict response.
Learn more about tumor biomarkers in ovarian cancer.
