BRAF/MEK inhibition in NSCLC: mechanisms of resistance and how to overcome it
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Ioannis Tsamis [1] ; Georgia Gomatou [1] ; Stavroula Porfyria Chachali [1] ; Ioannis Panagiotis Trontzas [1] ; Vasileios Patriarcheas [1] ; Emmanouil Panagiotou [1] ; Elias Kotteas [1]
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[1] National and Kapodistrian University of Athens
National and Kapodistrian University of Athens
Dimos Athens, Grecia
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- Localización: Clinical & translational oncology, ISSN 1699-048X, Vol. 25, Nº. 1 (January), 2023, págs. 10-20
- Idioma: inglés
- Texto completo no disponible (Saber más ...)
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Resumen
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.
