Abstract 5439: Metastasis-enhancing protein KITENIN confers temozolomide resistance in glioblastoma with unmethylated MGMT via upregulation of cancer stem cell makers

Abstract

Abstract Background: Elevated expression of cancer stem cell (CSC) markers is linked with progression, poor survival, and treatment resistance in glioblastoma (GBM). Our prior work identified KAI1 COOH-terminal interacting tetraspanin (KITENIN) as key to GBM progression. We investigated its influence on temozolomide (TMZ) resistance in GBM through modulation of CSC markers. Methods: We examined KITENIN and CSC markers in TMZ-resistant GBM cells and patient-derived GBM cells, and assessed therapeutic responses to TMZ in mice implanted with KITENIN-modulated GBM cells. The correlation of these markers with clinical outcomes was analyzed using our cohort and The Cancer Genome Atlas (TCGA) data. Results: High KITENIN expression correlated positively with elevated CSC marker levels in human GBM samples and KITENIN-modulated GBM cells. Inhibition of KITENIN using usnic acid reduced tumor progression by decreasing CSC marker expression. Our data and TCGA analyses linked co-directional increase of these factors with tumor recurrence and shorter survival in GBM patients with unmethylated MGMT. This increase was also observed in TMZ-resistant cell lines with unmethylated MGMT. Implantation of KITENIN-overexpressing cells led to TMZ resistance in our mouse model, associated with co-directionally increased CD44 and ALDH1A1 expression. The link between KITENIN and CD44/ALDH1A1 could be inhibited by DKC2511, a novel KITENIN inhibitor, and T5244, a c-Fos/AP-1 inhibitor. Conclusion: KITENIN might contribute to TMZ resistance in GBM patients with unmethylated MGMT, potentially through AP-1 activation and subsequent upregulation of CSC markers. Hence, targeting KITENIN could provide a novel strategy to overcome TMZ resistance in GBM patients with unmethylated MGMT. Citation Format: Eun-Jeong Ahn, Yeong Jin Kim, Tae-Young Jung, Jae-Hyuk Lee, Joon Haeng Rhee, Kyung-Keun Kim, Sung Sun Kim, Nah Ihm Kim, Hangun Kim, Kyung-Sub Moon, Kyung-Hwa Lee. Metastasis-enhancing protein KITENIN confers temozolomide resistance in glioblastoma with unmethylated MGMT via upregulation of cancer stem cell makers [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 5439.