1. BRAF/MEK inhibition in NSCLC: mechanisms of resistance and how to overcome it
- Author
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Ioannis Tsamis, Georgia Gomatou, Stavroula Porfyria Chachali, Ioannis Panagiotis Trontzas, Vasileios Patriarcheas, Emmanouil Panagiotou, and Elias Kotteas
- Subjects
Proto-Oncogene Proteins B-raf ,Mitogen-Activated Protein Kinase Kinases ,Cancer Research ,Lung Neoplasms ,Oncology ,MAP Kinase Signaling System ,Carcinoma, Non-Small-Cell Lung ,Mutation ,Humans ,General Medicine ,Protein Kinase Inhibitors - Abstract
Targeted therapy for oncogenic genetic alterations has changed the treatment paradigm of advanced non-small cell lung cancer (NSCLC). Mutations in the BRAF gene are detected in approximately 4% of patients and result in hyper-activation of the MAPK pathway, leading to uncontrolled cellular proliferation. Inhibition of BRAF and its downstream effector MEK constitutes a therapeutic strategy for a subset of patients with NSCLC and is associated with clinical benefit. Unfortunately, the majority of patients will develop disease progression within 1 year. Preclinical and clinical evidence suggests that resistance mechanisms involve the restoration of MAPK signaling which becomes inhibition-independent due to upstream or downstream alterations, and the activation of bypass pathways, such as the PI3/AKT/mTOR pathway. Future research should be directed to deciphering the mechanisms of cancer cells' oncogenic dependence, understanding the tissue-specific mechanisms of BRAF-mutant tumors, and optimizing treatment strategies after progression on BRAF and MEK inhibition.
- Published
- 2022
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