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Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have improved the prognosis of advanced-stage non-small cell lung cancer (NSCLC) with ALK rearrangement, but resistance mechanisms limit their efficacy. We describe the case of a 63-year-old man with a stage cIVA -rearranged lung adenocarcinoma who developed a A598-T599insV mutation as a potential resistance mechanism to alectinib, a second-generation ALK TKI. He was treated with an association of BRAF and MEK inhibitors but death occurred two months after treatment initiation in a context of tumor progression and toxicity. Based on this first report of A598-T599insV mutation occurring in lung cancer, we discuss resistance mechanisms to ALK TKIs, implications of mutation in NSCLC, and A598-T599insV mutation in other cancers.
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http://dx.doi.org/10.3389/fonc.2022.985446 | DOI Listing |
Int J Mol Sci
July 2023
Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy.
The Food and Drug Administration (FDA) has approved MAPK inhibitors as a treatment for melanoma patients carrying a mutation in codon V600 of the BRAF gene exclusively. However, BRAF mutations outside the V600 codon may occur in a small percentage of melanomas. Although these rare variants may cause B-RAF activation, their predictive response to B-RAF inhibitor treatments is still poorly understood.
View Article and Find Full Text PDFFront Oncol
November 2022
Division of Pulmonology, Centre Hospitalier Universitaire de l'Université Catholique de Louvain (CHU UCL) Namur (Godinne Site), Université Catholique de Louvain, Yvoir, Belgium.
Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have improved the prognosis of advanced-stage non-small cell lung cancer (NSCLC) with ALK rearrangement, but resistance mechanisms limit their efficacy. We describe the case of a 63-year-old man with a stage cIVA -rearranged lung adenocarcinoma who developed a A598-T599insV mutation as a potential resistance mechanism to alectinib, a second-generation ALK TKI. He was treated with an association of BRAF and MEK inhibitors but death occurred two months after treatment initiation in a context of tumor progression and toxicity.
View Article and Find Full Text PDFCase Rep Oncol
November 2019
Department of Oncology, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden.
Approximately 50% of patients with metastatic melanoma harbor an activating BRAF mutation. Tumors with activating mutation gene proliferate excessively and can be treated with targeted BRAF-inhibitors in combination with MEK inhibitors. The most common BRAF mutation occurs at amino acid position 600.
View Article and Find Full Text PDFMelanoma Res
October 2017
aDepartment of General Medical Oncology bDepartment of Human Genetics, Center for Human Genetics cDepartment of Pathology dDepartment of Oncological Surgery eDepartment of Dermatology, University Hospitals KU Leuven, Leuven fDepartment of Hematology and Medical Oncology, ;CHR East Belgium, Verviers,
Concurrent BRAF-MEK inhibition improves clinical outcomes in patients with advanced BRAF V600E/K-mutant melanoma. There is currently less evidence for the efficacy of this treatment in patients with rare BRAF non-V600E/K genotypes. We report on two patients with rare BRAF exon 15 mutations - BRAF A598_T599insV and V600_K601delinsE - obtaining clinical benefit and a radiological response to inhibitors directed against the mitogen-activated protein kinase pathway.
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