• Transl Res · Feb 2023

    Radiation combined with KRAS-MEK inhibitors enhances anticancer immunity in KRAS-mutated tumor models.

    • Yawen Zheng, Yanan Liu, Fang Zhang, Chen Su, Xiaozheng Chen, Mingyan Zhang, Meili Sun, Yuping Sun, and Ligang Xing.
    • Department of Oncology, Central hospital affiliated to Shandong First Medical University, Jinan, Shandong, P. R. China; Department of Radiation Oncology, Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, P. R. China; Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong, P. R. China; Research Center of Translational Medicine, Laboratory Animal Center, Central hospital affiliated to Shandong First Medical University, Jinan, Shandong, P. R. China.
    • Transl Res. 2023 Feb 1; 252: 799079-90.

    AbstractKRAS mutation is a common driver in solid tumors, and KRAS-mutated tumors are relatively resistant to radiotherapy. Therefore, we investigated the combined effect of radiation and KRAS-MEK inhibitors (AMG510 and trametinib) in KRAS-mutated tumors. The expression of programmed death-ligand 1 (PD-L1), major histocompatibility complex (MHC) class I molecules, and cytokines in KRAS-mutated cell lines was assessed using flow cytometry, western blot analysis, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay. In vivo, tumor growth, T cell infiltration, and gene sequencing analyses were conducted in 2 murine KRAS-mutated models. Both AMG510 and trametinib decreased the radiation-induced increase in PD-L1 expression. Radiation and trametinib additively induced the expression of CXCL10 and CXCL11 cytokines and MHC class I in murine CT26 and LLC cell lines. The combination of trametinib and radiation controlled tumor growth and induced more infiltration of CD4+ and CD8+ T cells in vivo, wherein tumor inhibition function and the survival period of mice could be reduced by CD8+ and/or CD4+ T cell depletion. The expression levels of immune-related genes also increased in the combination therapy group. Our results indicate that KRAS-MEK inhibitors in combination with radiotherapy can enhance antitumor immunity, providing new therapeutic strategies for KRAS-mutated tumors.Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

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