Therapeutic Resistance and Clinical Drug Failure in Hepato-Pancreatic-Biliary Cancers

Hepato-pancreatic-biliary (HPB) cancers, which include cancers of the liver, gallbladder, bile ducts, and pancreas, represent a major global health burden. Despite advances in early detection, surgical techniques, and systemic therapies, long-term survival outcomes for many HPB cancers remain poor. A critical factor underlying these unfavourable outcomes is the development of therapeutic resistance, which frequently leads to clinical drug failure.Therapeutic resistance in HPB cancers can be broadly categorized as intrinsic (primary) resistance and acquired (secondary) resistance. Intrinsic resistance refers to the insensitivity of tumor cells to a given therapy, often due to genetic, epigenetic, or microenvironmental factors present before treatment initiation. In contrast, acquired resistance develops over time in initially responsive tumors, driven by adaptive cellular changes under therapeutic pressure. These forms of resistance involve interactions between tumor cells, the surrounding microenvironment, and systemic host factors.At the molecular level, resistance mechanisms are multifactorial and include alterations in drug targets, activation of alternative signaling pathways, increased drug efflux, enhanced DNA repair capacity, and dysregulation of apoptosis. Tumor heterogeneity, both between tumors and within the same tumor, complicates treatment response, as various subpopulations may respond differently to therapy. Additionally, the tumor microenvironment, including stromal cells, immune components, hypoxia, and extracellular matrix interactions, plays a pivotal role in modulating therapeutic response and promoting resistance.Clinical drug failure is often the ultimate manifestation of these resistance mechanisms. It limits the efficacy of conventional chemotherapies and also poses challenges to targeted therapies and immunotherapies. In recent years, advances in genomics, proteomics, and systems biology have enhanced our understanding of therapeutic resistance and supported the development of novel treatment strategies, including combination therapies, adaptive treatment approaches, and precision medicine guided by predictive biomarkers. However, translating these discoveries into sustained clinical benefit remains an ongoing challenge. A better understanding of resistance pathways and clinically relevant biomarkers is therefore essential to improve patient outcomes in hepato-pancreatic-biliary cancers.Therapeutic resistance remains a major challenge in the treatment of hepato-pancreatic-biliary cancers, leading to reduced effectiveness of standard therapies and frequent clinical drug failure. The goal of this Research Topic is to understand the underlying mechanisms of resistance; to identify targets, molecular pathways involved in acquired resistance, and biomarkers for therapeutic resistance; and to identify strategies to improve treatment response and patient outcomes.Topics of interest include, but are not limited to:● Mechanisms underlying therapeutic resistance in hepato-pancreatic-biliary cancers ● Role of the tumor microenvironment in promoting resistance to chemotherapy, targeted therapy, and immunotherapy ● Impact of cancer heterogeneity on treatment response and drug resistance ● Identification of targets, molecular pathways involved in acquired resistance, and biomarkers for therapeutic resistance ● Clinical patterns and prevalence of drug failure in hepato-pancreatic-biliary cancer patients ● Emerging strategies to overcome resistance, including combination therapies and novel drug targets ● Advances in personalized and precision medicine approaches to improve treatment outcomes ● Evaluation of current treatment limitations and the development of more effective therapeutic interventions Please note: Manuscripts consisting solely of bioinformatics, computational analysis, or predictions of public databases which are not accompanied by validation (independent clinical or patient cohort, or biological validation in vitro or in vivo, which are not based on public databases) are not suitable for publication in this journal.Dr. Srushti Sodha (Topic Coordinator) is a Senior Scientist at Sanofi.Topic Editors declare that they have no conflicts of interest. Topic editors: Kaushik Neogi, Satish Rojekar, Binglin Sui Source: https://www.frontiersin.org/research-topics/80402/therapeutic-resistance-and-clinical-drug-failure-in-hepato-pancreatic-biliary-cancers