CXCR4-Targeted Necrosis-Inducing Peptidomimetic for Treating Breast Cancer

Triple-negative breast cancer is an aggressive subtypewith a highrecurrence rate, potential for metastasis, and a poor prognosis. Thechemokine receptor, CXCR4, is a promising molecular target in breastcancer therapy. Here, we have developed a CXCR4-targeted antitumorpeptidomimetic (named CTCE-KLAK), which is a fusion of the CXCR4 receptorantagonist CTCE-9908 and the D-form of proapoptotic peptide (KLAKLAK)(2), for the treatment of breast cancer. First, we investigatedthe in vitro antitumor activity of CTCE-KLAK againstvarious breast cancer cells and noncancerous mammary epithelial cells.CTCE-KLAK showed cell-selective cytotoxicity and induced rapid necroticcell death in breast cancer cells but not in normal cells. In contrast,unconjugated peptides such as the carboxylate analogues of CTCE-9908and (D)(KLAKLAK)(2) were not cytotoxic to thesecells. The tumor selectivity of CTCE-KLAK for cytotoxic activity dependson its internalization into tumor cells. There was no cleavage ofcaspase-3, caspase-7, or PARP1 in CTCE-KLAK-treated cells. In addition,cell death by CTCE-KLAK was not prevented by z-VAD-fmk, a pan-caspaseinhibitor that inhibits cisplatin-induced cell death. These data indicatethat the CTCE-KLAK conjugate is a cell-selective inducer of necrosis.Furthermore, we evaluated the in vivo antitumor activityof CTCE-KLAK in the 4T1 mouse metastatic breast cancer model. Intravenousadministration of CTCE-KLAK significantly inhibited tumor growth andlung metastasis. Together, these findings suggest that the necrosis-inducingpeptidomimetic CTCE-KLAK is a promising CXCR4-targeted agent for treatingtriple-negative breast cancer.

Automated summary

A CXCR4-targeted antitumor peptidomimetic (CTCE-KLAK) was developed and showed cell-selective cytotoxicity against breast cancer cells and induced rapid necrotic cell death. In a mouse model, CTCE-KLAK significantly inhibited tumor growth and lung metastasis, highlighting its potential as a promising agent for treating triple-negative breast cancer.