Anti-EGFR aptamer exhibits direct anti-cancer effects in NSCLC cells harboring EGFR L858R mutations

Abstract

AbstractNon-small cell lung cancer (NSCLC) adenocarcinoma (LUAD) is a leading cause of death worldwide. Activating mutations in the tyrosine kinase domain of the oncogene epidermal growth factor receptor (EGFR) are responsible for ∼10-50% of all LUAD cases. Although EGFR tyrosine kinase inhibitors (TKIs) have been effective in prolonging NSCLC patient survival and quality of life, acquired resistance mechanisms and disease progression are inevitable. Contemporary second- and third-line treatments, such as immunotherapy, remain ineffective for these patients, presenting a clear and unmet need for alternative or adjuvant therapeutics for the treatment of mutant EGFR positive NSCLC. Here we show that an anti-EGFR aptamer (EGFRapt) decreases viability of NSCLC cell lines harboring the L858R ± T790M mutation in EGFR but not cell lines harboring wild-type or exon 19 deletions. In a humanized xenograft mouse model of NSCLC,EGFRaptdecreased tumor burden compared to controls when delivered intratumorally over multiple doses. To elucidate the mechanism by whichEGFRaptexerts these effects, we monitored cellular processes associated with kinase-dependent and kinase-independent mechanisms and found that the anti-cancer effects ofEGFRaptare cell line dependent, inhibiting cellular proliferation in one cell line and inducing cell death in another. Post hoc transcriptomics analysis supported these findings and provided additional mechanistic insights. Overall, these data establish thatEGFRapthas direct anti-cancer activity in mutant EGFR positive NSCLC via targetable mechanisms that are independent of existing approaches, and they provide a foundation for further development of nucleic acid-based therapies that target EGFR.