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SCI 5 December 2024 FGTI-2734 Inhibits ERK Reactivation to Overcome Sotorasib Resistance in KRAS G12C Lung Cancer (Journal of Thoracic Oncology, IF: 21.0) Aslamuzzaman Kazi, Hitesh Kumar Kantilal Vasiyani, Deblina Ghosh, Dipankar Bandyopadhyay, Rachit D. Shah, Vignesh Vudatha, Jose Trevino, Said M. Sebti CORRESPONDENCE TO: Sebti@vcuhealth.org ABSTRACT 摘要 KRAS G12C targeted therapies, such as sotorasib, represent a major breakthrough, but overall response rates and progression-free survival for patients with KRAS G12C lung cancer are modest due to the emergence of resistance mechanisms involving adaptive reactivation of ERK, which requires wild-type (WT) HRAS and NRAS membrane localization. Here, we demonstrate that the dual farnesyltransferase (FT) and geranylgeranyltransferase-1 (GGT-1) inhibitor FGTI-2734 inhibits WT RAS membrane localization and sotorasib-induced ERK feedback reactivation, and overcomes sotorasib adaptive resistance. The combination of FGTI-2734 and sotorasib is
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