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

Yawen Zheng1, Yanan Liu2, Fang Zhang3

  • 1Department 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.

Translational Research : the Journal of Laboratory and Clinical Medicine
|August 10, 2022
PubMed

Insights

Combining KRAS-MEK inhibitors with radiotherapy enhances antitumor immunity in KRAS-mutated tumors. This approach improves T cell infiltration and controls tumor growth, offering new therapeutic strategies.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • KRAS mutations are prevalent drivers in solid tumors.
  • KRAS-mutated tumors exhibit resistance to radiotherapy.
  • Targeting KRAS is crucial for effective cancer treatment.

Purpose of the Study:

  • To investigate the combined effects of radiation and KRAS-MEK inhibitors (AMG510, trametinib) on KRAS-mutated tumors.
  • To assess the impact on immune markers like PD-L1, MHC class I, and cytokines.
  • To evaluate therapeutic efficacy in preclinical models.

Main Methods:

  • In vitro analysis of cell lines using flow cytometry, Western blot, qPCR, and ELISA.
  • In vivo studies in murine models assessing tumor growth and T cell infiltration.
  • Gene sequencing and immune cell depletion experiments.

Main Results:

  • Both AMG510 and trametinib reduced radiation-induced PD-L1 expression.
  • Radiation and trametinib additively increased CXCL10, CXCL11, and MHC class I expression.
  • Combination therapy controlled tumor growth and increased CD4+/CD8+ T cell infiltration, which was essential for tumor inhibition.

Conclusions:

  • KRAS-MEK inhibitors combined with radiotherapy enhance antitumor immunity.
  • This combination presents a promising therapeutic strategy for KRAS-mutated solid tumors.
  • Targeting KRAS pathways alongside radiation may overcome treatment resistance.

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