Targeting Stromal-Mediated Resistance Mechanisms in Oncogenic KRAS-Driven Pancreatic Ductal Adenocarcinoma

Jincheng Han (Advisor: Ronald DePinho, MD)

          Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with oncogenic KRAS mutations driving both tumor initiation and maintenance. Despite recent breakthroughs in KRAS-targeted therapies, the rapid emergence of resistance mechanisms limits their clinical efficacy. This dissertation investigates three interconnected aspects of PDAC biology and therapeutic targeting in the context of oncogenic KRAS. First, the thesis demonstrates that stromal-derived Neuregulin 1 (NRG1) activates upregulated ERBB2/3 receptors on cancer cells following KRAS inhibition, establishing a critical resistance pathway. Second, optimize tissue dissociation methodology was proposed for PDAC specimens, overcoming barriers created by the dense desmoplastic stroma to enable more effective isolation and characterization of tumor and stromal components. Last, the therapeutic potential of targeting the Hedgehog pathway in KRAS-mutant PDAC was investigated. Collectively, these findings advance understanding of tumor-microenvironment interactions in PDAC and provide a framework for novel combination therapeutic strategies targeting both oncogenic drivers and stromal resistance mechanisms.

Advisory Committee:

• Ronald DePinho, MD, Chair
• Daniel Frigo, PhD
• Jian Hu, PhD
• Stephanie Watowich, PhD
• Haoqiang Ying, MD, PhD

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