Abstract 3858: Therapeutic targeting of cofilin-1 phosphorylation by peptidomimetics inhibits lung cancer metastasis

Abstract Background: The main challenges in the clinical management of lung cancer are distant metastasis and recurrence. Targeting the destabilization of actin dynamics has become a critical approach to slowing the rapid proliferation of tumor cells. However, a specific class of anti-metastatic drugs is still being uncovered. Methods: The analysis of gene expression of ADF/cofilin family by public database in clinically relevant. Combination of the endogenous protein level of CFL-1, its phosphorylation status, and cellular invasion activity in various lung cancer cell lines. We used synthetic peptide to interfere LIMK/CFL-1 regulatory pathway to produced anti-metastatic and survival benefits in a xenograft lung cancer model. Furthermore, the biological characteristics of peptide labeled with metal radionuclide both in vitro and in vivo were also be evaluated. Results: Over-expression of cofilin-1 (CFL-1) gene was associated with the incidence and survival rate of lung adenocarcinoma using the in-silico analysis. CFL-1 proteins were also differentially elevated in various NSCLC cell lines. Notably, we found that the phosphorylation level of CFL-1 at serine 3 (Ser3), rather than the total CFL-1, was better correlated with the invasion potential of NSCLC cells. Here, we developed synthetic CFL-1 mimetic peptides (CMP) to inhibit endogenous CFL-1 phosphorylation and evaluated their effects using highly metastatic NSCLC cells. The SPECT/CT imaging demonstrated that CMP labeled with 99mTc can be detected in an orthotopic lung tumor. Furthermore, CMP can act as a competitive decoy of cofilin kinase, demonstrating anti-metastatic effects and prolonged survival in a xenograft model, with no significant toxicity observed. Conclusion: This study demonstrates that the phosphorylation level of CFL-1 at serine 3 is strongly correlated with the metastatic potential of lung cancer, and interfering with its phosphorylation could be a promising strategy for lung cancer treatment. Citation Format: Min-Ying Lin, Jyh-Der Leu, Chun-Yi Wu, Yi-Jang Lee. Therapeutic targeting of cofilin-1 phosphorylation by peptidomimetics inhibits lung cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3858.