Abstract 3082: Activation mevalonate pathway via HMGCS2 introduced resistance to molecular targeted therapy for cancer

Introduction: Recently, some oncogenic driver mutations found in any kinds of cancer. NTRK fusion is one of the oncogenic driver mutations express in any kinds of malignancy tumors and neurotrophic tropomyosin receptor kinase (NTRK) tyrosine kinase inhibitors (TKIs) is specific treatment for cancer harboring NTRK fusion. We investigated resistance mechanism of cancer harboring NTRK fusion to NTRK-TKI. Method: We established resistant cells to NTRK-TKIs (larotrectinib, entrectinib and selitrectinib) using KM12 harboring NTRK fusion. We investigated resistant cells for finding resistant mechanism to NTRK-TKI. Results: Whole exome sequence and microarray analysis conducted to resistant cells (KM12-LR, KM12-ER, and KM12-SR). Only KM12-LR have G595R as resistant solvent front mutation previously reported. We confirmed the overexpression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) in resistant cell lines from result of microarray, western blotting and quantitative RT-PCR. SREBP2 and PPARα which associated mevalonate pathway showed lower expression correlated HMGCS2 expression in resistant cells. After knocking down of HMGCS2, sensitivity to NTRK-TKI recovered in KM12-ER and KM12-SR. Mevalonic acid reintroduced NTRK-TKI resistance in KM12-ER and KM12-SR. after knocking down HMGCS2. Simvastatin and silibinin showed synergic effect with NTRK-TKIs to resistant cells, and delayed emergence of resistance in KM12 cells. In vivo study, resistant tumor to NTRK-TKI created in mice showed HMGCS2 over expression. NTRK-TKI and simvastatin reduced resistant tumor growth compared with entrectinib alone in vivo. Conclusion: Activation mevalonate pathway via HMGCS2 overexpression introduced resistance to NTRK-TKI. It found novel resistance mechanism to molecular targeted therapy. Statin showed possibly useful for overcoming resistance mechanism introduced by HMGCS2. Citation Format: Yasuhiro Kato. Activation mevalonate pathway via HMGCS2 introduced resistance to molecular targeted therapy for cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3082.