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Updated: Jun 2, 2025

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
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E203K mutation in MAP2K1 (MEK1) causes acquired resistance to PD-1 blockade but responds to trametinib: a case report

Weibing Leng1, Guixia Wei1, Leiming Sheng1

  • 1Colorectal Cancer Center, Sichuan University West China Hospital, Chengdu, China; Department of Medical Oncology, Cancer Center, Sichuan University West China Hospital, Chengdu, China.

Chinese Clinical Oncology
|January 14, 2025
PubMed
Abstract

Insights

Epstein-Barr virus-associated gastric cancer (EBVaGC) can develop resistance to immunotherapy. A MEK1 mutation acquired during treatment can be targeted with MEK inhibitors like trametinib for durable responses.

Area of Science:

  • Oncology
  • Immunotherapy
  • Molecular Biology

Background:

  • Epstein-Barr virus-associated gastric cancer (EBVaGC) exhibits high lymphocytic infiltration, suggesting immunotherapy sensitivity.
  • Mechanisms of acquired resistance to programmed cell death protein 1 (PD-1) blockade in EBVaGC remain understudied.
  • Understanding resistance is crucial for developing effective treatment strategies.

Observation:

  • A patient with EBVaGC achieved a near-complete response to chemotherapy plus the anti-PD-1 antibody Sintilimab.
  • Acquired resistance to PD-1 blockade emerged after radiotherapy, rendering subsequent Sintilimab treatment ineffective.
  • Tumor re-biopsy identified a secondary gain-of-function mutation in MAP2K1 (MEK1 E203K) in the resistant tumors.

Findings:

  • Aberrant activation of the mitogen-activated protein kinase (MAPK) pathway is a significant mechanism of immunotherapy resistance.
  • The MEK1 E203K mutation is directly implicated in acquired resistance to immune checkpoint inhibitors (ICIs).
  • Targeting the MEK1 E203K mutation with the MEK inhibitor trametinib resulted in a rapid and durable response.

Implications:

  • This case provides clinical evidence for MEK1 mutations driving ICI resistance in EBVaGC.
  • MEK inhibitors represent a promising therapeutic strategy for EBVaGC patients with acquired MEK1 mutations.
  • Further research into MAPK pathway alterations in immunotherapy resistance is warranted.
Keywords:
MAP2K1 (MEK1)case reportresistance to programmed cell death protein 1 blockade (resistance to PD-1 blockade)trametinib

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