Abstract 4370: Synthetic cell penetrating RAS-binding peptide for the treatment of RAS mutated cancer

Abstract The RAS-RAF-ERK1/2 signaling pathway plays a critical role in cancer progression and is a primary target for anticancer drug development, given its frequent activation in various human cancers. MAPK, a key molecule within this pathway, is vital for eukaryotic cells to process external stimuli, leading to cancer cell proliferation. The MDA-MB-231 cell line, which represents triple-negative breast cancer, carries a G13D KRAS mutation, rendering it resistant to numerous treatments. This mutation drives abnormal MAPK pathway activation, fueling tumor progression. To address this, a synthetic cell-penetrating peptide called RAS-binding peptide (RBP) was designed to selectively bind RAS with high affinity in MDA-MB-231 cells. Experimental results revealed that RBP effectively inhibited RAS-RAF interaction, leading to reduced cell proliferation and suppression of ERK1/2 phosphorylation in MDA-MB-231 cells. Additionally, RBP significantly decreased cell migration and invasion, indicating potential anti-metastatic properties. In both chicken egg and mouse xenograft models, RBP treatment markedly inhibited tumor growth and metastasis. Histopathological analysis further demonstrated enhanced immune cell infiltration, while immunohistochemistry confirmed reduced expression of Ki-67, a marker for tumor cell proliferation. Collectively, these findings highlight RBP as a promising therapeutic candidate for targeting RAS-driven cancer by inhibiting tumor growth and metastasis. Citation Format: Gookjin Yoon, Beom Soo Jo, Dong Woo Lee, Moonsil Choi, Eui Kyun Jeong, Hoo Cheol Lee, Yu-Bin Kim, Sanghui Seok, Yoon Shin Park, Jue-Yeon Lee, Chong Pyung Chung, Yoon Jeong Park. Synthetic cell penetrating RAS-binding peptide for the treatment of RAS mutated cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4370.