Abstract 351: Quaratusugene ozeplasmid mediated TUSC2 upregulation in EML4-ALK bearing non-small cell lung carcinoma can induce cellular apoptosis

Abstract

Abstract Anaplastic Lymphoma Kinase (ALK), a potent oncogenic driver in Non-Small Cell Lung Carcinoma (NSCLC), is found to be rearranged and fused to Echinoderm microtubule-associated protein-like 4 (EML4), contributing to approximately 5% of NSCLC as a distinct clinicopathological subset. Tumors bearing the EML4-ALK fusion are sensitive to ALK Tyrosine Kinase Inhibitors (TKIs), that form the first and second line of treatment for these patients. However, ALK+ lung cancers develop resistance to ALK inhibitors, creating the need for newer treatment strategies in ALK+ NSCLC. Tumor Suppressor Candidate 2 (TUSC2) is a tumor suppressor gene that is known to have low endogenous expression in NSCLC in general but data on TUSC2 in ALK+ lung cancers are not available. Quaratusugene ozeplasmid, developed by Genprex, is an immunogene therapy that upregulates TUSC2 expression in cancer cells by delivering the functional TUSC2 gene. It consists of the TUSC2 gene expressing plasmid encapsulated in non viral lipid nanoparticles. We evaluated TUSC2 expression in 3 ALK+ cell lines, both before and after exposure to quaratusugene ozeplasmid and to a TUSC2-containing plasmid. Controls were non-ALK+ cell lines and transfection with a plasmid containing no insert. Our studies in ALK+ lung cancer reveal that overexpressing TUSC2 using quaratusugene ozeplasmid treatment of ALK+ lung cancer cell lines is able to suppress colony formation by 50%, the effect being more significant than using a TUSC2-containing plasmid. Furthermore, we have observed a robust pro-apoptotic response to TUSC2 expression in ALK+ NSCLC, as both quaratusugene ozeplasmid and TUSC2-containing plasmid induced an increase in caspase 3/7 activity in the cancer cells, accompanied by an increase in cleaved PARP expression. Taken together, our data indicate that overexpression of TUSC2 in ALK+ NSCLC cell lines with quaratusugene ozeplasmid or with TUSC2-containing plasmid is effective in decreasing growth and proliferation through the activation of apoptotic pathways and warrants further investigation as an anti-ALK NSCLC strategy. Citation Format: Ananya Banerjee, Neeke Busette, Mark S. Berger, Matthew B. Soellner, Angel Qin, Sofia D. Merajver, Nathan M. Merrill. Quaratusugene ozeplasmid mediated TUSC2 upregulation in EML4-ALK bearing non-small cell lung carcinoma can induce cellular apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 351.