BRAF V600E Mediates Crizotinib Resistance and Responds to Dabrafenib and Trametinib in a ROS1-Rearranged Non-Small Cell Lung Cancer: A Case Report.

Abstract

Crizotinib, a multitargeted MET/ALK/ROS1 tyrosine kinase inhibitor, has been approved for the treatment of ROS1 fusion-positive non-small cell lung cancers (NSCLCs). However, "on-target" or "off-target" resistance alterations often emerge that confer the drug resistance. Patients with ROS1-rearranged NSCLC who develop crizotinib resistance, especially those acquiring "off-target" resistance mutations, still lack effective therapeutic options for after crizotinib treatment. Herein, we reported a patient with stage IVb lung adenocarcinoma harboring ROS1 fusion, who acquired a BRAF V600E and lost the ROS1 fusion after progression on crizotinib. It was deduced that the V600E may originate from a subclone with an extremely low fraction that was independent of ROS1 fusion-positive cells. The patient was subsequently treated with dabrafenib and trametinib combination and achieved a partial response lasting for more than 6 months. Our study revealed that BRAF V600E can confer the crizotinib resistance in ROS1 fusion-positive NSCLC and presented the first case showing that the treatment with dabrafenib and trametinib can serve as an effective option for later-line treatment for this molecular-defined subgroup. KEY POINTS: Patients with ROS1-rearranged non-small cell lung cancer (NSCLC) who acquire "off-target" resistance mutations to crizotinib still lack effective therapeutic options for after crizotinib treatment. This report describes the case of a patient with ROS1-rearranged NSCLC who acquired a BRAF V600E and lost the ROS1 fusion after crizotinib failure. The case was subsequently treated with dabrafenib and trametinib combination and achieved a partial response lasting for more than 6 months. This is the first article reporting that treatment with dabrafenib and trametinib may serve as an effective option for later-line treatment for patients harboring resistant BRAF V600E.

• Authors: Juan Li, Qifeng Wang, Jun Ge, Yuke Tian, Wenxiu Yao
• Journal: The oncologist (Oncologist) Vol. 26 Issue 12 Pg. e2115-e2119 (12 2021) ISSN: 1549-490X [Electronic] England
• PMID: 34516041 (Publication Type: Case Reports, Journal Article)
• Copyright: © 2021 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.

Chemical References

• Imidazoles
• Oximes
• Proto-Oncogene Proteins
• Pyridones
• Pyrimidinones
• trametinib
• Crizotinib
• Protein-Tyrosine Kinases
• ROS1 protein, human
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• dabrafenib

Topics

• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics)
• Crizotinib (therapeutic use)
• Drug Resistance, Neoplasm
• Humans
• Imidazoles
• Lung Neoplasms (drug therapy, genetics)
• Oximes
• Protein-Tyrosine Kinases (genetics)
• Proto-Oncogene Proteins (genetics)
• Proto-Oncogene Proteins B-raf (genetics)
• Pyridones
• Pyrimidinones