The K-Ras(G12D)-inhibitory peptide KS-58 suppresses growth of murine CT26 colorectal cancer cell-derived tumors

• Published in: Scientific reports Vol. 12; no. 1; p. 8121
• Main Authors: Sakamoto, Kotaro, Lin, Bangzhong, Nunomura, Kazuto, Izawa, Takeshi, Nakagawa, Shinsaku
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.05.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154; 631/154/1438; 631/154/436; 631/154/556; 631/154/570; 631/67; 631/67/1059; 631/67/1504; 631/67/395; Animals; Antitumor activity; Apoptosis; CD8 antigen; Cell death; Cell Line, Tumor; Cell Proliferation; Clinical trials; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Drug delivery; Humanities and Social Sciences; K-Ras protein; Lung cancer; Metastases; Mice; Monoclonal antibodies; multidisciplinary; Mutant Proteins - genetics; Mutants; Mutation; Pancreatic cancer; PD-1 protein; PD-L1 protein; Peptides; Peptides - therapeutic use; Phosphorylation; Proto-Oncogene Proteins p21(ras) - genetics; Regulatory approval; Science; Science (multidisciplinary); Tumors; Xenografts
• DOI: 10.1038/s41598-022-12401-3
• ISSN: 2045-2322

Mutations in the cell proliferation regulator K-Ras are found with a variety of cancer types, so drugs targeting these mutant proteins could hold great clinical potential. Very recently, a drug targeting the K-Ras(G12C) mutant observed in lung cancer gained regulatory approval and several clinical trials are currently underway to examine the efficacy of this agent when combined with other drugs such as a monoclonal antibody inhibitor of programmed cell death 1 receptor (anti-PD-1). Alternatively, there are currently no approved drugs targeting K-Ras(G12D), the most common cancer-associated K-Ras mutant. In 2020, we described the development of the K-Ras(G12D) inhibitory bicyclic peptide KS-58 and presented evidence for anticancer activity against mouse xenografts derived from the human pancreatic cancer cell line PANC-1 stably expressing K-Ras(G12D). Here, we show that KS-58 also possess anticancer activity against mouse tumors derived from the colorectal cancer cell line CT26 stably expressing K-Ras(G12D). Further, KS-58 treatment reduced phosphorylation of ERK, a major downstream signaling factor in the Ras pathway, confirming that KS-58 inhibits K-Ras(G12D) function. Unexpectedly; however, KS-58 did not show additive or synergistic anticancer activity with mouse anti-PD-1. Morphological analysis and immunostaining demonstrated no obvious differences in CD8 + cells infiltration or PD-L1 expression levels in CT26-derived tumors exposed to monotherapy or combination treatment. Nonetheless, KS-58 demonstrated reasonable stability in blood ( t 1/2 ≈ 30 min) and no obvious systemic adverse effects, suggesting clinical potential as a lead molecule against colorectal cancer.