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Unveiling the resistance to therapies in pancreatic ductal adenocarcinoma
Ashu Shah1, Koelina Ganguly1, Sanchita Rauth1
1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
Abstract:
Despite the ongoing advances in interventional strategies (surgery, chemotherapy, radiotherapy, and immunotherapy) for managing pancreatic ductal adenocarcinoma (PDAC), the development of therapy refractory phenotypes remains a significant challenge. Resistance to various therapeutic modalities in PDAC emanates from a combination of inherent and acquired factors and is attributable to cancer cell-intrinsic and -extrinsic mechanisms. The critical determinants of therapy resistance include oncogenic signaling and epigenetic modifications that drive cancer cell stemness and metabolic adaptations, CAF-mediated stromagenesis that results in ECM deposition altered mechanotransduction, and secretome and immune evasion. We reviewed the current understanding of these multifaceted mechanisms operating in the PDAC microenvironment, influencing the response to chemotherapy, radiotherapy, and immunotherapy regimens. We then describe how the lessons learned from these studies can guide us to discover novel therapeutic regimens to prevent, delay, or revert resistance and achieve durable clinical responses.
Insights
Pancreatic cancer (PDAC) exhibits therapy resistance due to complex intrinsic and extrinsic factors. Understanding these mechanisms is key to developing novel treatments for durable responses.
Area of Science:
- Oncology
- Cancer Biology
- Translational Medicine
Background:
- Pancreatic ductal adenocarcinoma (PDAC) remains challenging despite advances in surgery, chemotherapy, radiotherapy, and immunotherapy.
- Therapy resistance is a major obstacle, stemming from both inherent and acquired factors within the tumor microenvironment.
Purpose of the Study:
- To review the multifaceted mechanisms driving therapy resistance in PDAC.
- To explore how understanding these resistance mechanisms can inform the development of novel therapeutic strategies.
Main Methods:
- Comprehensive literature review of current research on PDAC therapy resistance.
- Analysis of intrinsic and extrinsic factors contributing to treatment failure.
- Examination of the role of the tumor microenvironment, including cancer-associated fibroblasts (CAFs) and immune evasion.
Main Results:
- Therapy resistance in PDAC is driven by oncogenic signaling, epigenetic modifications, cancer stemness, metabolic adaptations, CAF-mediated stromagenesis, and immune evasion.
- These mechanisms are interconnected and operate within the complex PDAC microenvironment.
- The tumor microenvironment significantly influences responses to chemotherapy, radiotherapy, and immunotherapy.
Conclusions:
- A thorough understanding of PDAC resistance mechanisms is crucial for overcoming treatment challenges.
- Targeting these multifaceted resistance pathways offers potential for developing novel therapeutic regimens.
- Future strategies should focus on preventing, delaying, or reverting resistance to achieve durable clinical responses in PDAC patients.
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