Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer · 2024
FGTI-2734 Inhibits ERK Reactivation to Overcome Sotorasib Resistance in KRAS G12C Lung Cancer.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Kazi Aslamuzzaman, Vasiyani Hitesh, Ghosh Deblina, Bandyopadhyay Dipankar, Shah Rachit D, Vudatha Vignesh, Trevino Jose, Sebti Said M
Аннотация
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.
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.