Τίτλος:
BRAF/MEK inhibition in NSCLC: mechanisms of resistance and how to overcome it
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2022, The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).
Συγγραφείς:
Tsamis, I.
Gomatou, G.
Chachali, S.P.
Trontzas, I.P.
Patriarcheas, V.
Panagiotou, E.
Kotteas, E.
Περιοδικό:
Clinical and Translational Oncology
Εκδότης:
Springer Science and Business Media Deutschland GmbH
Λέξεις-κλειδιά:
B Raf kinase; B Raf kinase inhibitor; binimetinib; cobimetinib; cyclin dependent kinase 4; dabrafenib; encorafenib; K ras protein; mammalian target of rapamycin; mitogen activated protein kinase; mitogen activated protein kinase kinase inhibitor; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; protein kinase B; protein serine threonine kinase; selumetinib; trametinib; transcription factor Yap1; vemurafenib; B Raf kinase; BRAF protein, human; mitogen activated protein kinase kinase; protein kinase inhibitor, Akt/mTOR signaling; anaplastic thyroid carcinoma; cancer inhibition; cell proliferation; colorectal cancer; disease exacerbation; Erdheim Chester disease; gene mutation; genetic screening; human; MAPK signaling; melanoma; molecularly targeted therapy; neurofibromatosis type 1; non small cell lung cancer; phase 1 clinical trial (topic); phase 2 clinical trial (topic); Pi3K/Akt signaling; review; Review; signal transduction; thyroid cancer; tumor growth; tumor immunity; genetics; lung tumor; metabolism; mutation; pathology, Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf
DOI:
10.1007/s12094-022-02849-0
