E203K mutation in MAP2K1 (MEK1) causes acquired resistance to PD-1 blockade but responds to trametinib: a case report

被引:0
|
作者
Leng, Weibing [1 ,2 ]
Wei, Guixia [1 ,2 ]
Sheng, Leiming [1 ,2 ]
Jiang, Dan [3 ]
Qiu, Meng [1 ,2 ]
机构
[1] Sichuan Univ, West China Hosp, Colorectal Canc Ctr, 37 Guoxue Lane, Chengdu 610041, Peoples R China
[2] Sichuan Univ, West China Hosp, Canc Ctr, Dept Med Oncol, Chengdu, Peoples R China
[3] Sichuan Univ, West China Hosp, Dept Pathol, Chengdu, Peoples R China
关键词
resistance to programmed cell death protein 1 blockade (resistance to PD-1 blockade); trametinib; case report; EPSTEIN-BARR-VIRUS; GASTRIC-CANCER; MICROSATELLITE INSTABILITY; BIOMARKER; SURVIVAL;
D O I
10.21037/cco-24-61
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: Epstein-Barr virus-associated gastric cancer (EBVaGC) is characterized by higher lymphocytic infiltration, which predicts sensitivity to immunotherapy. However, there are few studies investigating the mechanisms of acquired resistance to programmed cell death protein 1 (PD-1) blockade and its subsequent treatment strategies for EBVaGC. Case Description: We describe the case of a patient with EBVaGC who was initially treated with first- line chemotherapy plus Sintilimab, a fully humanized anti-PD-1 monoclonal antibody, resulting in a near- complete response. However, the acquired resistance to the immunotherapy treatment emerged shortly after consolidating radiotherapy, and subsequent second-line chemotherapy plus Sintilimab proved ineffective, confirming the true acquired resistance to PD-1 blockade. Re-biopsy of the treatment-resistant tumors revealed that a secondary gain-of-function mutation in mitogen-activated protein kinase kinase 1 (MAP2K1/ MEK1) E203K had been acquired. Subsequently, the patient received an off-label MEK inhibitor trametinib and achieved a rapid and durable response. Conclusions: This study highlights the aberrant activation of the mitogen-activated protein kinase (MAPK) pathway as another important mechanism of resistance to immunotherapy. This case provides direct clinical evidence that MEK1 E203K is involved in resistance to immune checkpoint inhibitors (ICIs). Furthermore, for the first time, the MEK inhibitor trametinib has shown promising results in treating tumors with this mutation.
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页数:9
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