BRAF/MEK inhibition in NSCLC: mechanisms of resistance and how to overcome it.
Ioannis TsamisGeorgia GomatouStavroula Porfyria ChachaliIoannis Panagiotis TrontzasVasileios PatriarcheasEmmanouil PanagiotouElias KotteasPublished in: Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico (2022)
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.
Keyphrases
- advanced non small cell lung cancer
- signaling pathway
- small cell lung cancer
- pi k akt
- ejection fraction
- wild type
- newly diagnosed
- metastatic colorectal cancer
- prognostic factors
- transcription factor
- copy number
- chronic kidney disease
- stem cells
- gene expression
- brain metastases
- dendritic cells
- mesenchymal stem cells