Sensitive methods for screening of the MEK1 gene mutations in patients with central nervous system metastases of non-small cell lung cancer

Abstract

BackgroundThe mitogen-activated protein kinases 1 and 2 (MEK1, MEK2) are fundamental partners in the RAS–RAF–MEK–ERK pathway that is involved in regulation of cell proliferation, differentiation and survival. Downregulation of the MEK cascades has been implicated in acquiring of the malignant phenotype in various cancers. Somatic mutations in MEK1 gene (substitutions K57N, Q56P, D67N) were described in <1 % of non-small cell lung cancer (NSCLC) and they were more commonly reported in adenocarcinoma patients with current or former smoking status.Materials and methodsIn the following study, we assessed the MEK1 gene mutations in 145 FFPE tissue samples from central nervous system (CNS) metastases of NSCLC using HRM-PCR and ASP-qPCR techniques. The studied group was heterogeneous in terms of histopathology and smoking status. The prevalence of the MEK1 gene mutation was correlated with the occurrence of mutations in KRAS, EGFR, DDR2, PIK3CA, NRAS, HER2, AKT1 and PTEN genes.ResultsUsing HRM and ASP-qPCR methods we identified one (0.7 %; 1/145) MEK1 substitution (Q56P) in CNS metastases of NSCLC. The mutation was identified in a single, 50-year-old, current smoking men with adenocarcinoma (1.25 %; 1/80 of all adenocarcinomas).ConclusionsAccording to the current knowledge, the incidence of MEK1 gene mutation in CNS metastatic lesion of NSCLC is the first such report worldwide. The analysis of gene profile in cancer patients may extend the scope of molecularly targeted therapies used both in patients with primary and metastatic tumors of NSCLC.

MAP2K1 K57N Conferred an Acquired Resistance to Furmonertinib, Dabrafenib and Trametinib Combined Therapy in Advanced Lung Adenocarcinoma with EGFR Mutation and BRAF V600E

“…The brain is often a common site for NSCLC metastasis, as well as a frequent location for the development of secondary drug resistance. 15 Mizuno et al reported that MAP2K1 K57N was identified as a RAFregulated mutation, and suggesting its potential association with resistance to RAF and MEK inhibitors in vitro. 16 This study further supports our conjecture that MAP2K1 K57N is a secondary drug resistance mutation.…”

Case report: Dual dabrafenib and trametinib therapy for treating BRAF V600E mutated lung adenocarcinoma with BRCA2 germline mutation post multiline progression

“…MEK1/2 are phosphorylated and activated by its upstream RAF kinases. Previous studies have indicated that KRAS or BRAF mutations are sensitive to MEK inhibitors ( 8 ). Besides, the resistance of BRAF V600 mutants to BRAF inhibitors may be caused by activating mutations of NRAS or KRAS or upregulation of receptor tyrosine kinases, which conferred sensitivity to MEK inhibition ( 9 , 10 ).…”

Evolutionary history of MEK1 illuminates the nature of cancer and RASopathy mutations

“…Early approaches to simultaneous sequencing of multiple genes of Ras/MAPK signaling pathways have yielded hundreds of mutations in MEK1 possibly associated with RASopathies and cancer. For example, germline MEK1 mutations have been reported in patients with cardiofaciocutaneous (CFC) syndrome (11)(12)(13), and somatic mutations have been identified in melanoma (14)(15)(16), lung cancer (17,18), gastric cancer (19), colon carcinoma (20), ovarian cancer (21), hairy cell leukemia (22), Langerhans Cell Histiocytosis (LCH) and the non-LCH (23)(24)(25). Due to the central role of MEK1 in the Ras/MAPK pathway signaling, it is a common target for highly selective inhibitors, such as Cobimetinib and Trametinib, that are used in cancer treatment (26)(27)(28)(29)(30).…”