Peptides targeting PIP4K2A : A novel therapeutic strategy for PTEN-deficient cancer

Tumor suppressor genes are essential for maintaining normal cellular development by restraining uncontrolled cell proliferation, and their inactivation is a hallmark of cancer progression. Peptide-based therapeutics have emerged as a promising treatment modality due to their high target specificity, biological activity, and favorable safety profiles. Among tumor suppressors, abnormalities in phosphatase and tensin homolog (PTEN) frequently arise from gene deletion, aberrant DNA methylation, or loss of functional protein expression. PTEN deficiency is observed in approximately 20-30% of human cancers and is closely associated with aggressive tumor behavior. Our previous studies identified that phosphatidylinositol-5-phosphate 4-kinase type 2 alpha (PIP4K2A) has been identified as a negative regulator of tumor progression in PTEN-deficient cancers. However, peptide-based therapeutic strategies targeting the PIP4K2A pathway have not fully investigated. In this study, we identified novel PIP4K2A-mimetic peptides derived from the N- and C-terminal regions of the human PIP4K2A protein. Peptide sensitivity assays were conducted to assess their effects on cancer cell viability according to PTEN status. In vitro analyses demonstrated that peptide-1 and peptide-2 exhibited significantly greater sensitivity in PTEN-deficient glioma cells (GL26) compared with PTEN wild-type glioma cells (GL261). Consistent with these findings, both peptides showed enhanced antitumor efficacy in patient-derived tumorospheroid models. Importantly, no significant toxicity was observed in normal liver organoids and human keratinocyte HaCaT cells, indicating favorable therapeutic selectivity. Notably, peptide-1 markedly suppressed tumor growth in vivo in a subcutaneous patient-derived xenograft model of PTEN-deficient cancer. Collectively, these results identify peptide-1 as a promising peptide-based therapeutic candidate with selectivity for PTEN-deficient tumors and significant potential for clinical translation.