Abstract B024: SHP2-ProTAC Unleashes Potent Antitumor Efficacy against KRAS-Mutant Pancreatic Cancer

Background: Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with an overall 5-year survival rate of 5%-13% approximately. The AG regimen (nab-paclitaxel plus gemcitabine) remains the standard treatment for advanced and metastatic PDAC, offering a median survival of about [AL1] 8.5 months. KRAS-mutation occurs in 90% of PDAC, predominantly G12D (41%-44%), G12V (30%-32%), and G12R (13%-16%). Current FDA-approved KRAS inhibitors (AMG510 and MRTX-849) target KRAS-G12C, which represent merely 1-2% of PDAC cases. Furthermore, resistance mechanisms, including an added KRAS-Y96D, limited efficacy. SHP2, as a critical node in KRAS signaling by phosphatase-dependent and -independent way, represents an alternative therapeutic target. Thus, we developed TRD209, a SHP2-PROTAC rather than small molecular inhibitor, as a promising therapeutic approach for diverse KRAS mutated PDAC by inhibiting bifunctional SHP2. Methods: We assessed TRD209 efficacy using Cell Titer-Glo luminescent viability assay across 63 KRAS-mutant cell lines, including those harbored G12D, G12V, G12C, G12R, G12C/Y96D double-mutant. In vivo pharmacological profile was conducted in 3 models: a KP-4(KRAS-G12D) CDX xenograft, a neuroendocrine carcinoma of the pancreas (KRAS-G12R) PDX xenograft and a small cell neuroendocrine carcinoma of the pancreas (KRAS-Wild Type, poorly differentiated) PDX xenograft. Tumor growth inhibition (TGI) and tolerability were evaluated following subcutaneous administration at various doses. Results: TRD209 demonstrated dose-dependent anti-tumor activity in 52/63(83%) KRAS-mutant cell lines. Notably, a total of 14 cell-lines exhibited IC50 values below 20 nM, with 9/14(64%) harboring KRAS-G12D, indicating enhanced potency against KRAS-G12D cell lines. TRD209 maintained an IC50 of 17.3nM in AMG510-ressistent H358-G12C/Y96D double-mutant cell-line, while AMG510(KRAS-G12C inhibitor) and RMC-6236(pan-KRAS inhibitor) showed no efficacy at all. In vivo TRD209 demonstrated robust antitumor activities without inducing weight loss. In KP-4 xenograft models, 10 mg/kg (Q3D) TRD209 achieved >90% TGI. In PDAC(KRAS-G12R) PDX xenograft models, 2.5 mg/kg (QD) TRD209 produced >95% TGI. Notably, in small cell neuroendocrine carcinoma PDAC (KRAS-WT, poorly differentiated) PDX models, a lower dose of 0.3 mg/kg (QD) TRD209 achieved >99% TGI, suggesting sensitivity in this aggressive poorly differentiated PDAC. Conclusion: Our results indicated that TRD209, a novel SHP2-ProTAC, effectively inhibits the proliferation across diverse KRAS-mutant PDAC models, particularly efficacy against those harboring KRAS-G12D mutations. Moreover, it overcomes resistance to existing KRAS inhibitors and shows exceptional potency in neuroendocrine pancreatic tumors. These findings establish TRD209, a SHP2 degrader, as a promising therapeutic strategy for KRAS-mutant pancreatic cancer, potentially addressing the limitations of current therapies. This study was funded by Tianjin Education Commission Grant 2017KJ226. Citation Format: Junrong Liu, Liying Zhou, Wenming Li, Xiaobo Li. SHP2-ProTAC Unleashes Potent Antitumor Efficacy against KRAS-Mutant Pancreatic Cancer [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 B024.