Targeting <i>BRAF</i> Activation as Acquired Resistance Mechanism to EGFR Tyrosine Kinase Inhibitors in <i>EGFR</i>-Mutant Non-Small-Cell Lung Cancer
Osimertinib has become a standard of care in the first-line treatment of advanced-stage non-small-cell lung cancer (NSCLC) harboring exon 19 and 21 activating mutations in the <i>EGFR</i> gene. Nevertheless, the 18.9-month median progression-free survival emphasizes the fact that resista...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-09-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/13/9/1478 |
| _version_ | 1797517557165457408 |
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| author | Frank Aboubakar Nana Sebahat Ocak |
| author_facet | Frank Aboubakar Nana Sebahat Ocak |
| author_sort | Frank Aboubakar Nana |
| collection | DOAJ |
| description | Osimertinib has become a standard of care in the first-line treatment of advanced-stage non-small-cell lung cancer (NSCLC) harboring exon 19 and 21 activating mutations in the <i>EGFR</i> gene. Nevertheless, the 18.9-month median progression-free survival emphasizes the fact that resistance to osimertinib therapy is inevitable. Acquired resistance mechanisms to osimertinib in EGFR-driven NSCLC include <i>MET</i> amplification, <i>EGFR</i> C797S mutation, neuroendocrine differentiation, small-cell lung carcinoma histologic transformation, <i>PD-L1</i> and <i>KRAS</i> amplifications and <i>ESR1-AKAP12</i> and <i>MKRN1-BRAF</i> translocations, as well as <i>BRAF</i> V600 mutation. This last one represents 3% of the acquired resistance mechanisms to osimertinib. In this review, we discuss the rationale for EGFR/BRAF/MEK co-inhibition in the light of a clinical case of <i>EGFR</i>-mutant NSCLC developing a <i>BRAF</i> V600 mutation as an acquired resistance mechanism to osimertinib and responding to the association of osimertinib plus dabrafenib and trametinib. Additionally, we discuss the acquired resistance mechanisms to osimertinib plus dabrafenib and trametinib combination in that context. |
| first_indexed | 2024-03-10T07:18:12Z |
| format | Article |
| id | doaj.art-437c58a22c344ce7a1c117143ba3aa5a |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T07:18:12Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-437c58a22c344ce7a1c117143ba3aa5a2023-11-22T14:48:21ZengMDPI AGPharmaceutics1999-49232021-09-01139147810.3390/pharmaceutics13091478Targeting <i>BRAF</i> Activation as Acquired Resistance Mechanism to EGFR Tyrosine Kinase Inhibitors in <i>EGFR</i>-Mutant Non-Small-Cell Lung CancerFrank Aboubakar Nana0Sebahat Ocak1Institut de Recherche Expérimentale et Clinique (IREC), Pôle de Pneumologie, ORL et Dermatologie (PNEU), Université catholique de Louvain (UCLouvain), 1200 Brussels, BelgiumInstitut de Recherche Expérimentale et Clinique (IREC), Pôle de Pneumologie, ORL et Dermatologie (PNEU), Université catholique de Louvain (UCLouvain), 1200 Brussels, BelgiumOsimertinib has become a standard of care in the first-line treatment of advanced-stage non-small-cell lung cancer (NSCLC) harboring exon 19 and 21 activating mutations in the <i>EGFR</i> gene. Nevertheless, the 18.9-month median progression-free survival emphasizes the fact that resistance to osimertinib therapy is inevitable. Acquired resistance mechanisms to osimertinib in EGFR-driven NSCLC include <i>MET</i> amplification, <i>EGFR</i> C797S mutation, neuroendocrine differentiation, small-cell lung carcinoma histologic transformation, <i>PD-L1</i> and <i>KRAS</i> amplifications and <i>ESR1-AKAP12</i> and <i>MKRN1-BRAF</i> translocations, as well as <i>BRAF</i> V600 mutation. This last one represents 3% of the acquired resistance mechanisms to osimertinib. In this review, we discuss the rationale for EGFR/BRAF/MEK co-inhibition in the light of a clinical case of <i>EGFR</i>-mutant NSCLC developing a <i>BRAF</i> V600 mutation as an acquired resistance mechanism to osimertinib and responding to the association of osimertinib plus dabrafenib and trametinib. Additionally, we discuss the acquired resistance mechanisms to osimertinib plus dabrafenib and trametinib combination in that context.https://www.mdpi.com/1999-4923/13/9/1478<i>EGFR</i>-mutant NSCLC<i>BRAF</i> mutation<i>BRAF</i> fusiontargeted therapyresistance mechanismsosimertinib |
| spellingShingle | Frank Aboubakar Nana Sebahat Ocak Targeting <i>BRAF</i> Activation as Acquired Resistance Mechanism to EGFR Tyrosine Kinase Inhibitors in <i>EGFR</i>-Mutant Non-Small-Cell Lung Cancer Pharmaceutics <i>EGFR</i>-mutant NSCLC <i>BRAF</i> mutation <i>BRAF</i> fusion targeted therapy resistance mechanisms osimertinib |
| title | Targeting <i>BRAF</i> Activation as Acquired Resistance Mechanism to EGFR Tyrosine Kinase Inhibitors in <i>EGFR</i>-Mutant Non-Small-Cell Lung Cancer |
| title_full | Targeting <i>BRAF</i> Activation as Acquired Resistance Mechanism to EGFR Tyrosine Kinase Inhibitors in <i>EGFR</i>-Mutant Non-Small-Cell Lung Cancer |
| title_fullStr | Targeting <i>BRAF</i> Activation as Acquired Resistance Mechanism to EGFR Tyrosine Kinase Inhibitors in <i>EGFR</i>-Mutant Non-Small-Cell Lung Cancer |
| title_full_unstemmed | Targeting <i>BRAF</i> Activation as Acquired Resistance Mechanism to EGFR Tyrosine Kinase Inhibitors in <i>EGFR</i>-Mutant Non-Small-Cell Lung Cancer |
| title_short | Targeting <i>BRAF</i> Activation as Acquired Resistance Mechanism to EGFR Tyrosine Kinase Inhibitors in <i>EGFR</i>-Mutant Non-Small-Cell Lung Cancer |
| title_sort | targeting i braf i activation as acquired resistance mechanism to egfr tyrosine kinase inhibitors in i egfr i mutant non small cell lung cancer |
| topic | <i>EGFR</i>-mutant NSCLC <i>BRAF</i> mutation <i>BRAF</i> fusion targeted therapy resistance mechanisms osimertinib |
| url | https://www.mdpi.com/1999-4923/13/9/1478 |
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