BRAF mutations classes I, II, and III in NSCLC patients included in the SLLIP trial : The need for a new pre-clinical treatment rationale
Bracht, Jillian (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Karachaliou, Niki (Hospital Universitari Sagrat Cor. Institut Oncològic Rosell)
Bivona, Trever (University of California. Department of Medicine)
Lanman, Richard B. (Guardant Health)
Faull, Iris (Guardant Health)
Nagy, Rebecca J. (Guardant Health)
Drozdowskyj, Ana (PIVOTAL SL)
Berenguer, Jordi (Institut Universitari Quirón-Dexeus. Laboratori de Biologia Molecular)
Fernandez-Bruno, Manuel (Hospital Universitario Sagrat Cor. Institut Oncològic Rosell)
Molina-Vila, Miguel Ángel (Institut Universitari Quirón-Dexeus. Laboratori de Biologia Molecular)
Rosell, Rafael (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)

Fecha:	2019
Resumen:	BRAF V600 mutations have been found in 1-2% of non-small-cell lung cancer (NSCLC) patients, with Food and Drug Administration (FDA) approved treatment of dabrafenib plus trametinib and progression free survival (PFS) of 10. 9 months. However, 50-80% of BRAF mutations in lung cancer are non-V600, and can be class II, with intermediate to high kinase activity and RAS independence, or class III, with impaired kinase activity, upstream signaling dependence, and consequently, sensitivity to receptor tyrosine kinase (RTK) inhibitors. Plasma cell-free DNA (cfDNA) of 185 newly diagnosed advanced lung adenocarcinoma patients (Spanish Lung Liquid versus Invasive Biopsy Program, SLLIP, NCT03248089) was examined for BRAF and other alterations with a targeted cfDNA next-generation sequencing (NGS) assay (Guardant360®, Guardant Health Inc. , CA, USA), and results were correlated with patient outcome. Cell viability with single or combined RAF, MEK, and SHP2 inhibitors was assessed in cell lines with BRAF class I, II, and III mutations. Out of 185 patients, 22 had BRAF alterations (12%) of which seven patients harbored amplifications (32%) and 17 had BRAF mutations (77%). Of the BRAF mutations, four out of 22 (18%) were V600E and 18/22 (82%) were non-V600. In vitro results confirmed sensitivity of class III and resistance of class I and II BRAF mutations, and BRAF wild type cells to SHP2 inhibition. Concomitant MEK or RAF and SHP2 inhibition showed synergistic effects, especially in the class III BRAF-mutant cell line. Our study indicates that the class of the BRAF mutation may have clinical implications and therefore should be defined in the clinical practice and used to guide therapeutic decisions.
Ayudas:	European Commission 765492 European Commission 712949 Instituto de Salud Carlos III PIE16-00011 Instituto de Salud Carlos III PI14/01678
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	BRAF ; NSCLC ; SHP2 ; PTPN11 ; MEK ; MAPK
Publicado en:	Cancers, Vol. 11, Issue 9 (September 2019) , art. 1381, ISSN 2072-6694

DOI: 10.3390/cancers11091381
PMID: 31533235

13 p, 2.9 MB

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