Abstract 2889: Cartilage oligomeric matrix protein as a potential biomarker and therapeutic target of radiation resistance in NSCLC

Abstract

Abstract Despite recent advances in lung cancer treatment, the survival rate of non-small cell lung cancer (NSCLC) is ~57% largely due to treatment resistance. Cartilage Oligomeric Matrix Protein (COMP) has previously been implicated in promoting metastasis and is associated with poor survival outcomes in breast, prostate and colorectal cancers. Patients with prostate cancer and osteoarthritis (a condition characterized by elevated circulating COMP) had both increased tumor COMP expression and rate of metastasis. Additionally, elevated COMP expression, among others, was observed in a study that investigated the gene expression of invasive NSCLC cell lines, though association with COMP was not further studied. Therefore, COMP could potentially increase the metastatic potential for NSCLC and thus serve as a therapeutic target to reduce tumor aggressiveness. We performed proliferation and migration assays on NSCLC cell lines, A549 and NCI-H1975, treated with 2 µg/mL COMP to identify COMP’s role in NSCLC progression. Plated cells in monolayer were treated with either COMP (2µg/mL) or PBS (control), and then within each group received either: 1] one of two different inhibitors of COMP signaling (either the αᵥ integrin antagonist cilengitide (1µM), or the Src inhibitor PP2 (1µM)), or 2] no additional treatment. Replicates from each group then received 2Gy Cs137 γ-radiation, or no irradiation. Proliferation and migration were monitored via the IncuCyte ZOOM live-cell imaging system over a 48hr interval. Radiation alone reduced both proliferation (-22%, p<0.0001) and migration (-40%, p<0.01) of A549 cells. However, exogenous COMP treatment attenuated the effects of radiation, maintaining both A549 proliferation (19% vs irradiated control, p<0.05) and migration (91% vs irradiated control, p<0.0001). While the overall pattern for NCI-H1975 cells with/without COMP treatment was similar, the magnitude of the responses was reduced vs A549 cells and non-significant. In contrast, radiation resistance with COMP treatment was abrogated by exogenous treatment of both COMP inhibitors. Cilengitide treatment resulted in lower proliferation rates of the COMP treated, irradiated A549 (-16%, p<0.05) and NCI-H1975 cell lines (-58%, p<0.0001) vs COMP treatment alone, while PP2 reduced proliferation and migration rates for both irradiated and non-irradiated COMP treated cell lines (p<0.0001). PP2 treatment alone did not reduce migration rates of either irradiated control cell lines. In conclusion, COMP serves to radioprotect NSCLC in an undetermined manner, and could serve as both a prognostic biomarker for and therapeutic target against radiation resistance in patients with NSCLC. Support: Milton Raben Foundation Citation Format: Kaitlyn E. Reno, Sun H. Park, Michael K. Farris, Ryan T. Hughes, Joseph E. Moore, Chirayu M. Patel, Jeffrey S. Willey. Cartilage oligomeric matrix protein as a potential biomarker and therapeutic target of radiation resistance in NSCLC [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 2889.