Abstract A017: Dual Targeting of KRAS and Nutrient Scavenging via SDC1 Inhibition Offers a Promising Therapeutic Strategy in Pancreatic Cancer

Abstract Oncogenic KRAS is a central driver of pancreatic ductal adenocarcinoma (PDAC), and the development of KRASG12C inhibitors represents a key advance in targeted therapy. However, most patients experience disease progression due to acquired resistance. There is a critical need for therapeutic strategies that address KRAS-independent survival mechanisms and extend the efficacy of KRAS-targeted therapies. We identified the transmembrane heparan sulfate proteoglycan Syndecan-1 (SDC1) as a functional mediator of KRAS-driven metabolic adaptation. Acute genetic or pharmacologic KRAS inhibition reduces SDC1 localization on the plasma membrane; however, resistant PDAC cells restore membrane SDC1, enabling bypass signaling through receptor tyrosine kinases (RTKs) and macropinocytosis-mediated nutrient scavenging. Mechanistically, this process is driven by YAP1 activation, which suppresses ARF6 GTPase-activating proteins and increases ARF6 activity, promoting SDC1 membrane recycling. To exploit this vulnerability, we developed 22B, a novel human-specific monoclonal antibody targeting SDC1. 22B impairs PDAC growth in vitro and in vivo through two mechanisms: direct inhibition of macropinocytosis and induction of antibody-dependent cellular cytotoxicity (ADCC). In combination, 22B synergizes with KRAS inhibitors, chemotherapy, and immune checkpoint blockade to enhance anti-tumor effects. These findings support a dual-targeting strategy that disrupts both KRAS signaling and nutrient scavenging pathways. SDC1 is a viable therapeutic target whose inhibition not only suppresses tumor-intrinsic metabolic reprogramming but also re-sensitizes resistant tumors to KRAS blockade. Our study establishes the therapeutic rationale for combining KRAS and SDC1 inhibition to overcome resistance and improve outcomes in PDAC. Citation Format: Mitsunobu Takeda, Shuaitong Chen, Madelaine Skolastika. Theardy, Zecheng Yang1, Alexey Sorokin, Xiaofei Wang, Phuoc Nguyen, Preeti Kanikarla, Jun Yao, Yongkun Wei, Haoqiang Ying, Wantong Yao. Defining UHRF1 as a crucial factor in pancreatic cancer progression and treatment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A017.