Overcoming therapy resistance in pancreatic cancer: challenges and emerging strategies

Taymin du Toit-Thompson; Lionel Leck; Josef Gillson; Nick Pavlakis; Anthony J Gill; Jaswinder S Samra; Anubhav Mittal; Sumit Sahni

doi:10.1016/j.addr.2025.115647

Overcoming therapy resistance in pancreatic cancer: challenges and emerging strategies

Adv Drug Deliv Rev. 2025 Sep:224:115647. doi: 10.1016/j.addr.2025.115647. Epub 2025 Jul 9.

Authors

Taymin du Toit-Thompson¹, Lionel Leck¹, Josef Gillson¹, Nick Pavlakis², Anthony J Gill³, Jaswinder S Samra⁴, Anubhav Mittal⁵, Sumit Sahni⁶

Affiliations

¹ Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, St Leonards, Sydney, Australia.
² Faculty of Medicine and Health, University of Sydney, Australia; Northern Sydney Cancer Centre, Royal North Shore Hospital, St Leonards, NSW, Australia.
³ Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, St Leonards, Sydney, Australia; Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW 2065, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital St Leonards, NSW 2065, Australia.
⁴ Faculty of Medicine and Health, University of Sydney, Australia; Australian Pancreatic Centre, St Leonards, Sydney, Australia; Upper GI Surgical Unit, Royal North Shore Hospital and North Shore Private Hospital, Australia.
⁵ Faculty of Medicine and Health, University of Sydney, Australia; Australian Pancreatic Centre, St Leonards, Sydney, Australia; Upper GI Surgical Unit, Royal North Shore Hospital and North Shore Private Hospital, Australia; The University of Notre Dame Australia, Sydney, Australia.
⁶ Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, St Leonards, Sydney, Australia. Electronic address: sumit.sahni@sydney.edu.au.

PMID: 40645337
DOI: 10.1016/j.addr.2025.115647

Abstract

Pancreatic cancer (PC) is one of the deadliest types of cancer, with a 5-year survival rate of ∼12.5 %. It is expected to become the second leading cause of cancer-related deaths by 2030. Despite recent advances in treatment options by the advent of various targeted and immunotherapies, their benefits have not been actualized for PC patients and chemotherapy remains the mainstay systemic therapeutic option for these patients. However, the majority of PC tumors have a highly chemo-resistant phenotype, leading to therapeutic failure. This review provides a comprehensive overview of the established mechanisms related to chemoresistance in PC and provides insight into emerging theories, including the potential role of the microbiome in modulating therapeutic responsiveness. It further discusses potential opportunities to explore to overcome this critical clinical problem.

Keywords: Chemotherapy resistance; Pancreatic cancer; Systemic treatment; Therapeutic failure.

Publication types

Review

MeSH terms

Animals
Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Drug Resistance, Neoplasm* / drug effects
Humans
Immunotherapy
Pancreatic Neoplasms* / drug therapy
Pancreatic Neoplasms* / microbiology

Substances

Antineoplastic Agents