Abstract A178: Therapeutic potential of a p14ARF minimal domain peptide in non-small cell lung cancer

Abstract

Many current therapeutic efforts in cancer biology focus on inhibiting the function of aberrant oncogenes whose activities are known to increase proliferation and cell growth. Unfortunately, these efforts have had limited success in lung cancer, where the five-year survival rate remains unchanged. We sought a novel approach; rather than inhibiting oncogenes, we worked to reestablish the function of the p14ARF tumor suppressor in non-small cell lung cancer (NSCLC) to block tumor growth and proliferation. The p14ARF tumor suppressor is encoded by the CDKN2A gene and is the second most commonly mutated gene in NSCLC. p14ARF is known to play a fundamental role in preventing cancer progression by regulating senescence, apoptosis, and proliferation. Here, to determine the minimal functional domain of p14ARF, we generated a panel of p14ARF expression mutants, deleting various amino acids within the known functional and conserved domains of p14ARF. These mutants were then evaluated for their ability to function as wild type p14ARF. Through proliferative and transformative studies, we identified a 10-amino acid domain that is required for p14ARF function. New cell-penetrating peptide technology was employed to determine if these resides were sufficient to elicit antiproliferative effects on their own. We now show that this small region of ARF is capable of entering tumor cells when linked to a cell penetrating peptide. Moreover, this small cell penetrating ARF peptide retains all of ARF’s known tumor suppressor functions. Our findings provide evidence that small cell penetrating peptides are capable of inhibiting tumor cell growth and proliferation. These experiments also lay the foundation for more precise therapeutic peptide cancer treatments, ones that could be used to restore p14ARF tumor suppressor function.

Citation Format: Anna L Grobelny, Leonard B Maggi, Jason D Weber. Therapeutic potential of a p14ARF minimal domain peptide in non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A178.