Rat Sarcoma (RAS)-Protein-Targeting Synthetic Cell-Penetrating Peptide as an Anticancer Biomaterial

• DOI: 10.34133/bmr.0175
• Publication Date: 2025-03-19T17:37:10Z
• Authors: Gookjin Yoon; Jinsook Suh; Beom Soo Jo; Dong Woo Lee; Deogil Kim; Moonsil Choi; Eui Kyun Jeong; Hoo Cheol Lee; Hye Min Shin; Yu-Bin Kim; Sanghui Seok; Yoon Shin Park; Chong Pyung Chung; Jue-Yeon Lee; Yoon Jeong Park

Various bioactive materials, including peptides, have become potential candidates for slowing cancer growth and metastasis. Among bioactive peptides, a synthetic cell-penetrating peptide referred to as rat sarcoma (RAS)-binding peptide (RBP) was suggested as a potential entity that targets RAS with high affinity in MDA-MB-231 cancer cells. This RAS binding further inhibits the RAS–rapidly accelerated fibrosarcoma (RAF) protein–protein interaction. The current study revealed that RBP effectively suppresses proliferation and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation by disrupting the RAS–RAF interaction. This intervention not only inhibits cell migration and invasion but also has substantial potential for preventing metastasis. The RAS–RAF–ERK1/2 pathway is a key target for anticancer drug development because of frequent ERK and mitogen-activated protein kinase activation in human cancers. MDA-MB-231, a triple-negative breast cancer cell line, harbors a G13D Kirsten rat sarcoma viral oncogene homolog mutation, making it resistant to many drugs. In addition to its in vitro antitumor activity, RBP was identified as a potent antagonist that substantially arrests tumor growth and invasiveness in in vivo chicken egg and mouse xenograft tumor models. Notably, histopathological analyses revealed increased immune cell infiltration and decreased Ki-67 expression, confirming the ability of RBP to inhibit tumor cell proliferation. Taken together, these findings highlight RBP as a therapeutic anticancer biomaterial capable of impeding the progression and metastasis of RAS-mutated cancers.