RUNX3 regulates the susceptibility against EGFR-targeted non-small cell lung cancer therapy using 47 Sc-conjugated cetuximab

• Published in: BMC cancer Vol. 23; no. 1; p. 652
• Main Authors: Kim, Da-Mi, Lee, So-Young, Lim, Jae-Cheong, Cho, Eun-Ha, Park, Ul-Jae
• Format: Journal Article
• Language: English
• Published: England 12.07.2023
• Subjects: Antibodies, Monoclonal; Carcinoma, Non-Small-Cell Lung - drug therapy; Cetuximab - pharmacology; Cetuximab - therapeutic use; Core Binding Factor Alpha 3 Subunit; ErbB Receptors; Humans; Lung Neoplasms - drug therapy; Pentetic Acid; EGFR-expressing NSCLC; Radioimmunotherapy; Cetuximab; RUNX3; Scandium-47
• ISSN: 1471-2407

Radioimmunotherapy with cetuximab and conjugates with various radioisotopes is a feasible treatment option for different tumor models. Scandium-47 ( Sc), one of several β -particle-emitting radioisotopes, displays favorable physical and chemical properties for conjugation to monoclonal antibodies. However, the therapeutic efficacy of Sc in preclinical and clinical studies is largely unknown. Given that intrinsic alterations in tumors greatly contribute to resistance to anti-epidermal growth factor receptor (EGFR)-targeted therapy, research on overcoming resistance to radioimmunotherapy using cetuximab is required. Sc was produced by irradiation of a CaCO target at the HANARO research reactor in KAERI (Korea Atomic Energy Research Institute) and prepared by chromatographic separation of the irradiated target. Cetuximab was conjugated with Sc using the bifunctional chelating agent DTPA. Radiochemical purity was determined using instant thin-layer chromatography. The immunoreactivity of Sc-DTPA-cetuximab was evaluated using the Lindmo method and an in vitro cell-binding assay. The inhibitory effects of cetuximab and Sc-DTPA-cetuximab were confirmed using cell growth inhibition and BrdU cell proliferation assays. Differences in protein expression levels between cetuximab- and Sc-DTPA-cetuximab-treated cells were confirmed using western blotting. Complex formation between RUNX3 and DNA repair components was confirmed using immunoprecipitation and western blotting. Cetuximab induces cell cycle arrest and cell death in EGFR-overexpressing NSCLC cells. Radiolabeling of cetuximab with Sc led to increased therapeutic efficacy relative to cetuximab alone. Application of Sc-DTPA-cetuximab induced DNA damage responses, and activation of RUNX3 significantly enhanced the therapeutic efficacy of Sc-DTPA-cetuximab. RUNX3 mediated susceptibility to EGFR-targeted NSCLC therapy using Sc-DTPA-cetuximab via interaction with components of the DNA damage and repair machinery. Sc-DTPA-cetuximab promoted cell death in EGFR-overexpressing NSCLC cells by targeting EGFR and inducing DNA damage as a result of β irradiation emitted from the conjugated Sc. Activation of RUNX3 played a key role in DNA damage and repair processes in response to the ionizing radiation and inhibited cell growth, thus leading to more effective tumor suppression. RUNX3 can potentially moderate susceptibility to Sc-conjugated cetuximab by modulating DNA damage and repair process mechanisms.