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

  • Transl Res. 2023 Feb:252:79-90. doi: 10.1016/j.trsl.2022.08.005.
Yawen Zheng  1 ,  Yanan Liu  2 ,  Fang Zhang  3 ,  Chen Su  4 ,  Xiaozheng Chen  5 ,  Mingyan Zhang  2 ,  Meili Sun  4 ,  Yuping Sun  5 ,  Ligang Xing  6
Affiliations
  • 1. 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.
  • 2. 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.
  • 3. Department of Oncology, Central hospital affiliated to Shandong First Medical 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.
  • 4. Department of Oncology, Central hospital affiliated to Shandong First Medical University, Jinan, Shandong, P. R. China.
  • 5. 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.
  • 6. 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, Shandong Cancer Hospital and Institute, Shandong University, Jinan, Shandong, P. R. China. Electronic address: [email protected].
PMID: 35948200 DOI: 10.1016/j.trsl.2022.08.005
Abstract

KRAS 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.

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