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.

中文翻译：

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揭示胰腺导管腺癌对治疗的耐药性


尽管治疗胰腺导管腺癌 （PDAC） 的介入策略（手术、化疗、放疗和免疫疗法）不断取得进展，但治疗难治性表型的开发仍然是一个重大挑战。PDAC 对各种治疗方式的耐药性源于固有因素和后天因素的组合，可归因于癌细胞的内在和外在机制。治疗耐药性的关键决定因素包括驱动癌细胞干性和代谢适应的致癌信号传导和表观遗传修饰、导致 ECM 沉积改变机械转导的 CAF 介导的基质发生，以及分泌组和免疫逃逸。我们回顾了目前对 PDAC 微环境中运作的这些多方面机制的理解，这些机制影响对化疗、放疗和免疫治疗方案的反应。然后，我们描述了从这些研究中吸取的经验教训如何指导我们发现新的治疗方案来预防、延迟或逆转耐药性并实现持久的临床反应。