BRAF/MEK inhibition in NSCLC: mechanisms of resistance and how to overcome it

• Published in: Clinical & translational oncology Vol. 25; no. 1; pp. 10 - 20
• Main Authors: Tsamis, Ioannis, Gomatou, Georgia, Chachali, Stavroula Porfyria, Trontzas, Ioannis Panagiotis, Patriarcheas, Vasileios, Panagiotou, Emmanouil, Kotteas, Elias
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.01.2023
• Subjects: Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; MAP Kinase Signaling System; Medicine; Medicine & Public Health; Mitogen-Activated Protein Kinase Kinases - metabolism; Mutation; Oncology; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins B-raf - genetics; Review Article; MEK; BRAF; Targeted therapy; Non-small cell lung cancer; Resistance mechanisms
• ISSN: 1699-3055; 1699-3055
• DOI: 10.1007/s12094-022-02849-0

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.