Abstract C096: Targeting Syndecan1 to overcome acquired resistant to KRAS inhibitor in gastrointestinal cancer

Abstract

Abstract Development of treatment resistance is a major impediment to effective cancer therapy. KRASG12C inhibitors have been recently approved by FDA and specific inhibitors targeting additional KRAS mutations are under clinical and preclinical development. These KRAS oncogene-specific inhibitors (KRASi) represent a promising new targeted therapy for KRAS-driven cancer types. However, as is the case for most targeted therapies, majority of tumors that initially respond to KRASG12C inhibitor quickly develop resistant disease. Unfortunately, the underlying mechanisms of KRASi resistance remain to be fully elucidated. We employed various in vitro and in vivo preclinical model systems to explore the development of KRASi resistance. Our study demonstrated that the YAP1- Syndecan 1 (SDC1) axis as the major driver for the bypass of KRAS-dependence and targeting YAP1-SDC1 will overcome the acquired resistance to KRAS targeted therapy. We previously identified the membrane proteoglycan SDC1 as a KRAS downstream surrogate whose cell surface localization is tightly controlled by oncogenic KRAS signaling and is critical for KRAS-driven tumor development. Here, our analysis of KRAS driven genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC) and human pancreatic or colorectal cancer (CRC) cells with KRASG12C mutation discovered that, while cell surface SDC1 is reduced upon acute genetic or pharmacological of oncogenic KRAS, plasma membrane SDC1 is recovered in tumor cells that become resistant to KRAS inhibition (KRAS-bypass cells). Surface localization of SDC1 leads to the activation of multiple receptor tyrosine kinases (RTKs), resulting in the resistance to KRAS blockade. We further identified that the recovery of plasma membrane SDC1 in KRAS-bypass cells is driven by YAP1 oncogene, which mediates the transcription suppression of ARF6 GAPs, leading to the activation of ARF6, a small GTPase required for SDC1 membrane recycling. Genetic depletion of YAP1 or SDC1, as well as pharmacological inhibition of YAP1-SDC1 axis abolishes the tumorigenic activity of KRAS-bypass tumor cells and sensitizes KRAS-driven tumors to KRASi. Moreover, YAP1 and surface SDC1 are accumulated in CRC PDX models with acquired resistance to KRASG12C-inhibitor. Importantly, pharmacological targeting YAP1 significantly suppresses surface SDC1 in KRASi-resistant PDXs and sensitizes the tumors to KRASG12C-inhibitor. Taken together, our research identifies new actionable therapeutic targets and approaches to overcome resistance to KRAS inhibition, thus implicating the therapeutic potential to greatly improve the clinical outcome of patients with KRAS mutated cancers. Citation Format: Mitsunobu Takeda, Alexey Sorokin, Madelaine Theardy, Oluwadara Coker, Scott Kopetz, Haoqiang Ying, Giulio Draetta, Ronald A. DePinho, Wantong Yao. Targeting Syndecan1 to overcome acquired resistant to KRAS inhibitor in gastrointestinal cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C096.