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

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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.

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Authors and Affiliations

  1. Oncology Unit, Third Department of Internal Medicine, “Sotiria” General Hospital for Diseases of the Chest, National and Kapodistrian University of Athens, Messogion Ave 152, 11527, Athens, Greece

    Ioannis Tsamis, Georgia Gomatou, Ioannis Panagiotis Trontzas, Vasileios Patriarcheas, Emmanouil Panagiotou & Elias Kotteas

  2. 4th Department of Internal Medicine, “Atticon” General Hospital, National and Kapodistrian University of Athens, Athens, Greece

    Stavroula Porfyria Chachali

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  1. Ioannis Tsamis
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  2. Georgia Gomatou
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Tsamis, I., Gomatou, G., Chachali, S.P. et al. BRAF/MEK inhibition in NSCLC: mechanisms of resistance and how to overcome it. Clin Transl Oncol 25, 10–20 (2023). https://doi.org/10.1007/s12094-022-02849-0

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