<i>BRAF</i> Mutations Classes I, II, and III in NSCLC Patients Included in the SLLIP Trial: The Need for a New Pre-Clinical Treatment Rationale
<i>BRAF</i> 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 <i>...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2019-09-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/11/9/1381 |
| _version_ | 1797728567260348416 |
|---|---|
| author | Jillian Wilhelmina Paulina Bracht Niki Karachaliou Trever Bivona Richard B. Lanman Iris Faull Rebecca J. Nagy Ana Drozdowskyj Jordi Berenguer Manuel Fernandez-Bruno Miguel Angel Molina-Vila Rafael Rosell |
| author_facet | Jillian Wilhelmina Paulina Bracht Niki Karachaliou Trever Bivona Richard B. Lanman Iris Faull Rebecca J. Nagy Ana Drozdowskyj Jordi Berenguer Manuel Fernandez-Bruno Miguel Angel Molina-Vila Rafael Rosell |
| author_sort | Jillian Wilhelmina Paulina Bracht |
| collection | DOAJ |
| description | <i>BRAF</i> 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 <i>BRAF</i> 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 <i>BRAF</i> 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 <i>BRAF</i> class I, II, and III mutations. Out of 185 patients, 22 had <i>BRAF</i> alterations (12%) of which seven patients harbored amplifications (32%) and 17 had <i>BRAF</i> mutations (77%). Of the <i>BRAF</i> 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 <i>BRAF</i> mutations, and BRAF wild type cells to SHP2 inhibition. Concomitant MEK or RAF and SHP2 inhibition showed synergistic effects, especially in the class III <i>BRAF</i>-mutant cell line. Our study indicates that the class of the <i>BRAF</i> mutation may have clinical implications and therefore should be defined in the clinical practice and used to guide therapeutic decisions. |
| first_indexed | 2024-03-12T11:15:55Z |
| format | Article |
| id | doaj.art-a6fcd5443b7e40bdbed93580c4eb6492 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T11:15:55Z |
| publishDate | 2019-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-a6fcd5443b7e40bdbed93580c4eb64922023-09-02T02:01:23ZengMDPI AGCancers2072-66942019-09-01119138110.3390/cancers11091381cancers11091381<i>BRAF</i> Mutations Classes I, II, and III in NSCLC Patients Included in the SLLIP Trial: The Need for a New Pre-Clinical Treatment RationaleJillian Wilhelmina Paulina Bracht0Niki Karachaliou1Trever Bivona2Richard B. Lanman3Iris Faull4Rebecca J. Nagy5Ana Drozdowskyj6Jordi Berenguer7Manuel Fernandez-Bruno8Miguel Angel Molina-Vila9Rafael Rosell10Pangaea Oncology, Laboratory of Molecular Biology, Quirón-Dexeus University Institute, 08028 Barcelona, SpainPangaea Oncology, Laboratory of Molecular Biology, Quirón-Dexeus University Institute, 08028 Barcelona, SpainDepartment of Medicine, University of California, San Francisco, CA 94143, USAGuardant Health, Inc., Redwood City, CA 94063, USAGuardant Health, Inc., Redwood City, CA 94063, USAGuardant Health, Inc., Redwood City, CA 94063, USAPIVOTAL SL, 28023 Madrid, SpainPangaea Oncology, Laboratory of Molecular Biology, Quirón-Dexeus University Institute, 08028 Barcelona, SpainInstituto Oncológico Rosell (IOR), University Hospital Sagrat Cor, QuironSalud Group, 08029 Barcelona, SpainPangaea Oncology, Laboratory of Molecular Biology, Quirón-Dexeus University Institute, 08028 Barcelona, SpainPangaea Oncology, Laboratory of Molecular Biology, Quirón-Dexeus University Institute, 08028 Barcelona, Spain<i>BRAF</i> 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 <i>BRAF</i> 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 <i>BRAF</i> 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 <i>BRAF</i> class I, II, and III mutations. Out of 185 patients, 22 had <i>BRAF</i> alterations (12%) of which seven patients harbored amplifications (32%) and 17 had <i>BRAF</i> mutations (77%). Of the <i>BRAF</i> 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 <i>BRAF</i> mutations, and BRAF wild type cells to SHP2 inhibition. Concomitant MEK or RAF and SHP2 inhibition showed synergistic effects, especially in the class III <i>BRAF</i>-mutant cell line. Our study indicates that the class of the <i>BRAF</i> mutation may have clinical implications and therefore should be defined in the clinical practice and used to guide therapeutic decisions.https://www.mdpi.com/2072-6694/11/9/1381BRAFNSCLCSHP2PTPN11MEKMAPK |
| spellingShingle | Jillian Wilhelmina Paulina Bracht Niki Karachaliou Trever Bivona Richard B. Lanman Iris Faull Rebecca J. Nagy Ana Drozdowskyj Jordi Berenguer Manuel Fernandez-Bruno Miguel Angel Molina-Vila Rafael Rosell <i>BRAF</i> Mutations Classes I, II, and III in NSCLC Patients Included in the SLLIP Trial: The Need for a New Pre-Clinical Treatment Rationale Cancers BRAF NSCLC SHP2 PTPN11 MEK MAPK |
| title | <i>BRAF</i> Mutations Classes I, II, and III in NSCLC Patients Included in the SLLIP Trial: The Need for a New Pre-Clinical Treatment Rationale |
| title_full | <i>BRAF</i> Mutations Classes I, II, and III in NSCLC Patients Included in the SLLIP Trial: The Need for a New Pre-Clinical Treatment Rationale |
| title_fullStr | <i>BRAF</i> Mutations Classes I, II, and III in NSCLC Patients Included in the SLLIP Trial: The Need for a New Pre-Clinical Treatment Rationale |
| title_full_unstemmed | <i>BRAF</i> Mutations Classes I, II, and III in NSCLC Patients Included in the SLLIP Trial: The Need for a New Pre-Clinical Treatment Rationale |
| title_short | <i>BRAF</i> Mutations Classes I, II, and III in NSCLC Patients Included in the SLLIP Trial: The Need for a New Pre-Clinical Treatment Rationale |
| title_sort | i braf i mutations classes i ii and iii in nsclc patients included in the sllip trial the need for a new pre clinical treatment rationale |
| topic | BRAF NSCLC SHP2 PTPN11 MEK MAPK |
| url | https://www.mdpi.com/2072-6694/11/9/1381 |
| work_keys_str_mv | AT jillianwilhelminapaulinabracht ibrafimutationsclassesiiiandiiiinnsclcpatientsincludedintheslliptrialtheneedforanewpreclinicaltreatmentrationale AT nikikarachaliou ibrafimutationsclassesiiiandiiiinnsclcpatientsincludedintheslliptrialtheneedforanewpreclinicaltreatmentrationale AT treverbivona ibrafimutationsclassesiiiandiiiinnsclcpatientsincludedintheslliptrialtheneedforanewpreclinicaltreatmentrationale AT richardblanman ibrafimutationsclassesiiiandiiiinnsclcpatientsincludedintheslliptrialtheneedforanewpreclinicaltreatmentrationale AT irisfaull ibrafimutationsclassesiiiandiiiinnsclcpatientsincludedintheslliptrialtheneedforanewpreclinicaltreatmentrationale AT rebeccajnagy ibrafimutationsclassesiiiandiiiinnsclcpatientsincludedintheslliptrialtheneedforanewpreclinicaltreatmentrationale AT anadrozdowskyj ibrafimutationsclassesiiiandiiiinnsclcpatientsincludedintheslliptrialtheneedforanewpreclinicaltreatmentrationale AT jordiberenguer ibrafimutationsclassesiiiandiiiinnsclcpatientsincludedintheslliptrialtheneedforanewpreclinicaltreatmentrationale AT manuelfernandezbruno ibrafimutationsclassesiiiandiiiinnsclcpatientsincludedintheslliptrialtheneedforanewpreclinicaltreatmentrationale AT miguelangelmolinavila ibrafimutationsclassesiiiandiiiinnsclcpatientsincludedintheslliptrialtheneedforanewpreclinicaltreatmentrationale AT rafaelrosell ibrafimutationsclassesiiiandiiiinnsclcpatientsincludedintheslliptrialtheneedforanewpreclinicaltreatmentrationale |