Peptide inhibitors: Breaking cancer code

Abstract

Tumour signalling pathways play a pivotal role in tumorigenesis by controlling key cellular processes, including growth, proliferation, metastasis, and survival. Conventional treatments like chemotherapy often face limitations such as non-specific toxicity and drug resistance. Peptide inhibitors have gained attention as a promising therapeutic alternative due to their high selectivity in disrupting oncogenic pathways via protein-protein interactions (PPIs) and ligand binding. Currently, two out of 31 peptide-based cancer drugs have demonstrated signalling inhibition, with several others under investigation. However, challenges related to stability, delivery, and resistance persist, prompting innovations in peptide design, such as cyclisation and nanoparticle-based delivery systems. This review examines strategies to enhance peptide drug efficacy, explores the mechanisms by which peptide inhibitors target key pathways like the rat sarcoma protein (RAS) and mammalian target of rapamycin (mTOR) pathways, and highlights ongoing research on peptide-based interventions. Key examples include RAS-targeting peptides such as KRpep-2D, cyclo-CRVLIR, L5UR, RAS-binding peptide (RBP), the mutant KRAS peptide vaccine combined with Nivolumab and Ipilimumab, cyclorasin B4-27, and LUNA18, as well as mTOR-targeting peptides like P1_WT, PDHK1-241aa, TRIM1-269aa, and the micropeptide human small regulatory polypeptide of amino acid response (hSPAR). Among these, the mutant KRAS peptide vaccine (with Nivolumab and Ipilimumab) and LUNA18 demonstrate promising clinical potential and are currently undergoing trials.