Aug 2026· Therapeutic Advances in Medical Oncology· Vol 18· 0 citations· 75 references
Medicine
TL;DR
Continued translational research is therefore essential to identify predictive biomarkers and to optimize novel combination strategies to overcome resistance, as well as the integration of dynamic biomarkers and quantitative tools to define optimal treatment sequencing and improve patient outcomes in this challenging disease setting.
Abstract
Antibody-drug conjugates (ADCs) have emerged as a major therapeutic advance in ovarian cancer, particularly when platinum-based chemotherapy is not a treatment option. By selectively delivering potent cytotoxic payloads to tumor cells, ADCs such as mirvetuximab soravtansine (MIRV), targeting FRα, and trastuzumab deruxtecan (T-DXd), targeting HER2, have demonstrated clinically meaningful activity in selected populations. However, resistance to ADCs inevitably develops through diverse mechanisms, including payload resistance and target antigen downregulation. Continued translational research is therefore essential to identify predictive biomarkers and to optimize novel combination strategies. Beyond ADCs, other systemic approaches have demonstrated survival improvements in PROC even in biomarker-unselected populations, including the addition of the glucocorticoid receptor antagonist relacorilant to nab-paclitaxel and immune–chemotherapy combinations such as pembrolizumab plus paclitaxel with or without bevacizumab. Future directions aim to prioritize synergistic combinations to overcome resistance. This includes pairing ADCs with replication stress inhibitors like ATR inhibitors and WEE1 inhibitors or integrating them with next-generation immuno-oncology platforms such as bispecifics, T-cell engagers, and cancer vaccines, as well as the integration of dynamic biomarkers and quantitative tools to define optimal treatment sequencing and improve patient outcomes in this challenging disease setting.
Antibody-drug conjugates (ADCs) are one of the most significant advancements in modern cancer therapeutics. Combining the target selectivity of monoclonal antibodies with the cytotoxic potential of payloads, ADCs effectively kill cancer cells and offer hope to patients with even refractory cancer types. Beyond simply increasing the number of therapeutic options available for cancer patients, ADCs have become a powerful frontline agent in overcoming multidrug resistance (MDR). As one of the most challenging obstacles to effective cancer care, MDR is mediated by ATP-binding cassette (ABC) transporter-mediated drug efflux, target-based mutations, and dysregulated apoptosis. The clinical success of ADCs specifically engineered to overcome MDR, including in heterogeneous tumors and cancer cells that exhibit bypass signaling, is well established. This is especially evident with trastuzumab deruxtecan (T-DXd) in HER2-low, HER2-positive, and HER2-mutant cancers; sacituzumab govitecan (SG) in TROP2-expressing triple-negative breast cancer (TNBC) and urothelial carcinoma; and enfortumab vedotin in Nectin-4-positive bladder cancer. By overcoming MDR, ADCs have enabled more effective treatment algorithms across multiple malignancies. Most importantly, the clinical application of ADCs has become inextricably linked to cancer genomics. HER2 testing has evolved from a two-tiered system to a continuous spectrum including HER2-ultralow, HER2-low, HER2-positive, and ERBB2-mutant categories. Each of these categories exhibits different eligibility guidelines for ADC patient selection. As cancer cells continue to evolve and develop resistance to even ADCs through mutations and variants, researchers and clinicians have used pharmacogenomics to predict ADC response and resistance. To define the genomic architecture of ADC-resistant tumor subpopulations, single-cell transcriptomic studies and liquid biopsy approaches are being used to enable real-time examination of the tumor genome during ADC therapy, thereby optimizing treatment and circumventing resistance driven by emerging mutations and variants. This review provides a comprehensive analysis of the molecular structure of ADCs, the pharmacological principles underlying their potent cytotoxic activity against MDR cancer cells, the genomic and transcriptomic biomarkers that guide ADC patient selection, and the emerging resistance mechanisms that will shape the next generation of promising ADC development.
Ryan Li, Xiang Chen, Qinguo Huang et al.· Cancer Letters· 0 citations
Future research should prioritize tumor-selective linker design, novel payload development, bispecific and dual-payload ADC platforms, and rational combination strategies to overcome resistance and further improve the therapeutic index of ADCs in CRC.
L. Zeng, Yuanlin Zhu, Ke Zhang et al.· Biochemical Pharmacology· 0 citations
This review provides a comprehensive overview of chemotherapy-free strategies in ovarian cancer (OC). We first outline the foundational biomarkers guiding targeted therapy, including homologous recombination deficiency for PARP inhibitors (PARPi), angiogenic pathways for anti-angiogenic agents, the tumor immune microenvironment for immunotherapies, hormone receptors for endocrine approaches, and emerging targets for antibody-drug conjugates. We then organize therapeutic strategies by clinical setting (frontline, platinum-sensitive recurrent, and platinum-resistant recurrent) to align with clinical decision-making. Current challenges are also addressed, including acquired resistance to PARPi and anti-angiogenic agents, the impact of prior PARPi exposure on platinum sensitivity, and practical concerns such as drug safety and cost. Finally, we present a critical view highlighting key unanswered questions and future challenges, emphasizing the need for biomarker-driven patient selection, resistance-overcoming combinations, and next-generation therapeutic platforms. This review aims to provide a practical framework for navigating the current landscape and future directions of chemotherapy-free approaches in OC.
Caixia Jiang, Zhengyu Li· Critical reviews in oncology...· 0 citations
The rationale for targeting established and emerging antigens in non-small cell and small cell lung cancer, including HER2, TROP2, c-MET, HER3, CEACAM5, DLL3, and other promising targets currently under clinical investigation are discussed.
P. Paliogiannis, G. Fara, A. Zinellu et al.· Current Issues in Molecular...· 0 citations
Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is a marker of cancer stem-like cells frequently upregulated in colorectal cancer (CRC) with lower expression in normal tissues, making it a favorable target for antibody-drug conjugates (ADCs). ADCs combine antibody specificity with potent cytotoxic payloads to enhance efficacy while minimizing systemic toxicity. LGR5-targeting ADCs incorporating different payloads demonstrate strong initial tumor inhibition, yet tumors eventually recur due in part to LGR5 downregulation, necessitating more effective strategies to prevent relapse. We show treatment with chemotherapies or an LGR5-targeting ADC coupled to a topoisomerase 1 inhibitor payload (8E11-CPT2) reduces LGR5 levels and increases MET receptor expression and/or activation in CRC cells, supporting a therapeutic approach to target LGR5 and MET simultaneously. Accordingly, we engineered a MET-targeting ADC (ABT-700-SG3199) via site-specific conjugation of the anti-MET antibody telisotuzumab (ABT-700) with the DNA-crosslinking pyrrolobenzodiazepine (PBD) dimer SG3199. ABT-700-SG3199 exhibited superior potency and efficacy in CRC models compared to the clinical-stage MET-targeting ADCs ABBV-399 and ABBV-400, which use the same antibody backbone conjugated to different payloads. Treatment with ABT-700-SG3199 increased LGR5 expression, and the combination of ABT-700-SG3199 with 8E11-CPT2 enhanced CRC cell-killing efficacy, reinforcing the rationale for a dual-targeting approach. In patient-derived xenografts, combined administration of 8E11-CPT2 and ABT-700-SG3199 markedly delayed tumor relapse and prolonged survival compared with single-agent treatment. Taken together, these findings reveal a reciprocal regulation between MET and LGR5 in response to LGR5- or MET-targeting ADCs in CRC models and support a LGR5/MET dual-targeting therapeutic strategy to enhance efficacy and potentially overcome resistance and relapse.
Shraddha Subramanian, Peyton C. High, Cara Guernsey-Biddle et al.· bioRxiv· 0 citations
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of solid tumors, yet only a limited subset of patients achieves durable disease control. While China has emerged as a major contributor to global ICI development, a comprehensive synthesis of recent trial data and resistance mechanisms is urgently needed to guide clinical practice. This review examines the evolving landscape of ICI‐based combination therapies, including regimens that combine ICI with chemotherapy, targeted therapy, antibody–drug conjugates, antiangiogenic agents, and radiotherapy, which have expanded first‐line treatment options across multiple solid tumors and, in selected settings, have improved disease control or survival beyond historical monotherapy benchmarks. An in‐depth analysis of the molecular mechanisms underlying primary and acquired resistance to ICIs is then provided, drawing on recent advances in multiomics. Building on this framework, emerging, mechanism‐matched strategies designed to overcome specific resistance nodes are critically evaluated. Finally, the promise of integrating spatial transcriptomics and artificial intelligence to help shift ICI therapy from empirical combination toward mechanism‐guided precision immuno‐oncology is discussed. By bridging the gap between clinical evidence and molecular insights, this review offers a perspective that may help accelerate the rational design of next‐generation ICI‐based strategies and improve patient outcomes.
