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. 2025 Mar;20(3):331-344.
doi: 10.1016/j.jtho.2024.11.022. Epub 2024 Nov 26.

FGTI-2734 Inhibits ERK Reactivation to Overcome Sotorasib Resistance in KRAS G12C Lung Cancer

Aslamuzzaman Kazi  1 , Hitesh Vasiyani  1 , Deblina Ghosh  1 , Dipankar Bandyopadhyay  2 , Rachit D Shah  3 , Vignesh Vudatha  3 , Jose Trevino  3 , Said M Sebti  4
Affiliations

FGTI-2734 Inhibits ERK Reactivation to Overcome Sotorasib Resistance in KRAS G12C Lung Cancer

Aslamuzzaman Kazi et al. J Thorac Oncol. 2025 Mar.

Abstract

Introduction: 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 HRAS and NRAS membrane localization.

Methods and results: Here, we demonstrate that the dual farnesyltransferase and geranylgeranyltransferase-1 inhibitor FGTI-2734 inhibits wild-type RAS membrane localization and sotorasib-induced ERK feedback reactivation, and overcomes sotorasib adaptive resistance. The combination of FGTI-2734 and sotorasib is synergistic at inhibiting the viability and inducing apoptosis of KRAS G12C lung cancer cells, including those highly resistant to sotorasib. FGTI-2734 enhances sotorasib's anti-tumor activity in vivo leading to significant tumor regression of a patient-derived xenograft (PDX) from a patient with KRAS G12C lung cancer and several xenografts from highly sotorasib-resistant KRAS G12C human lung cancer cells. Importantly, treatment of mice with FGTI-2734 inhibited sotorasib-induced ERK reactivation in KRAS G12C PDX, and treatment of mice with the combination of FGTI-2734 and sotorasib was also significantly more effective at suppressing in vivo the levels of P-ERK in sotorasib-resistant human KRAS G12C lung cancer xenografts and the NSCLC PDX.

Conclusion: Our findings provide a foundation for overcoming sotorasib resistance and potentially improving the treatment outcomes of KRAS G12C lung cancer.

Keywords: FGTI-2734; Farnesyltransferase; Geranylgeranyltransferase-1; KRAS G12C; Resistance; Sotorasib; lung cancer.

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Conflict of interest statement

Disclosure The authors declare no conflict of interest.

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