Abstract An extracellular matrix has been demonstrated to be one of the substances that promote tumor cells to become driven by external stimuli to change their biology or malignancy. The main component of extracellular matrix, chondroitin sulfate, has been confirmed as a factor in the progression of tumors. Nevertheless, a great deal remains unknown regarding the precise mechanisms that drive Chondroitin sulfate production and how these details are communicated to cancer cells. According to our previous studies, the main enzyme responsible for Chondroitin sulfate synthesis, carbohydrate sulfotransferase 11 (CHST11), plays a crucial role in lung cancer cell metastatic spread. Nevertheless, the relationship between CHST11 expression and regulatory mechanism in response to lung cancer treatment is unclear, especially for tyrosine kinase inhibitor (TKI). A clinical correlation analysis was used in this study to identify molecules which were highly correlated with the overexpression of CHST11 and identified GPI-anchored protein semaphorin 7A (SEMA7A) as a candidate. According to the TCGA database, expression of upregulated SEMA7A is correlated with poor prognosis and cellular malignancy in lung cancer patients. A SEMA7A-based gene correlation analysis finds that the affected gene ontology is highly similar to CHST11, particularly integrin signaling, which may contribute to Gefitinib resistance. A GSEA analysis reveals a significant effect of CHST11 overexpression on mitotic spindle processes, some of which molecules are clinically relevant to CHST11 or SEMA7A. These molecules have been reported to be involved in TKI resistance events such as MARCKS, MYO1E, and PDLIM5. Based on the TCGA database, these molecules and integrins also display significant clinical relevance in lung cancer patients. A CHST11-mediated increase in SEMA7A in the mitotic spindle process of cells may serve as one of the possible means of reducing TKI-induced mitotic cell death, and thereby promoting the ability of lung cancer cells to become resistant to TKIs. Hence, targeting the CHST11-SEMA7A axis may offer a therapeutic strategy option that could be used to target drug resistance in lung cancers. [Keywords: CHST11, SEMA7A, Integrin, Drug resistant, Lung cancer] (Reference: https://pubmed.ncbi.nlm.nih.gov/35985204/; https://pubmed.ncbi.nlm.nih.gov/36181245/) Citation Format: Chien-Hsiu Chris Li, Ming-Hsien Chan, Yu-Chan Chang, Michael Hsiao. CHST11 mediated SEMA7A expression contributes to TKI resistant in lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3899.