Dual Inhibition of EGFR and BRAF Can Be Harmful in Patients Harboring an EGFR-Activating Mutation
Authors: Sekyung Oh, Jun Hyeok Lim, Nuri Park, Seohee Choi, Jeong-Seon Ryu
Journal: Journal of Thoracic Oncology (2020)

EGFR tyrosine kinase inhibitors (TKIs) are widely used to treat patients with non-small-cell lung carcinoma (NSCLC) who have mutations that activate the tyrosin kinase EGFR. Although EGFR-TKI treatment appears to be effective in reducing tumor mass in the beginning of therapy, the tumor eventually develops a resistance in most EGFR-NSCLC patients. Notably, a mutation altering a second site in the EGFR protein, T790M, accounts for the majority (∼60%) of the resistance to both the first-generation EGFR TKIs (e.g., gefitinib and erlotinib) and the second-generation EGFR TKIs (e.g., afatinib). Accordingly, the third-generation EGFR-TKI, osimertinib, was developed to target the EGFR T790M mutation and was recently approved as the "first"-line treatment for NSCLC patients with EGFR-activating mutations even before the arise of the EGFR T790M mutation.1Soria J.C. Ohe Y. Vansteenkiste J. et al.Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer.N Engl J Med. 2018; 378: 113-125Crossref PubMed Scopus (2701) Google Scholar In addition to the EGFR T790M mutation, either mutations, amplifications, or fusions of the genes affecting downstream and parallel signaling pathways constitute the remainder of the EGFR TKI resistance cases.2Mitsudomi T. BRAF fusion — another mechanism of acquired resistance to EGFR tyrosine kinase inhibitors.J Thorac Oncol. 2019; 14: 764-765Abstract Full Text Full Text PDF Scopus (1) Google Scholar These include oncogenic mutations in the genes encodingKRAS, NRAS, MEK, and PIK3CA proteins; amplifications of the genes encoding MAPK, HER2, and MET proteins; and fusions of the genes encoding ALK, FGFR3, NTRK1, and RET proteins with a gene of high-level expression. Thus, combined treatment of EGFR TKIs with relevant inhibitors could provide a reasonable option to overcome the resistance.3Tricker E.M. Xu C. Uddin S. et al.Combined EGFR/MEK inhibition prevents the emergence of resistance in EGFR-mutant lung cancer.Cancer Discov. 2015; 5: 960-971Crossref PubMed Scopus (159) Google Scholar Recent studies have shown that the serine/threonine kinase BRAF is activated due either to BRAF V600E mutation or to gene fusion in a subset of patients who are resistant to EGFR TKIs. Notably, such BRAF activation has not been reported in EGFR TKI treatment-naive patients but detected only in patients with an acquired EGFR TKI resistance, suggesting that BRAF activation can be selected de novo during EGFR TKI therapy. Hence, dual inhibition of EGFR and BRAF might be a reasonable treatment option to block the potential, unwanted activation of BRAF pathway, which could result from EGFR TKI therapy in the absence of prior BRAF activation. How potent or safe this approach is, however, remains unknown. Thus, we examined the treatment effect of the BRAF inhibitor dabrafenib on the growth of such NSCLC cell lines as A549 (EGFR wild-type), H1650 (EGFR ex19del), HCC827 (EGFR ex19del), and PC9 (EGFR ex19del) in the presence or absence of the EGFR TKI afatinib.4Planchard D. Besse B. Groen H.J.M. et al.Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non–small cell lung cancer: an open-label, multicentre phase 2 trial.Lancet Oncol. 2016; 17: 984-993Abstract Full Text Full Text PDF PubMed Scopus (592) Google Scholar We noted that dabrafenib alone has little effect on the growth of all the cell lines with EGFR wild-type or the activating mutation ex19del (Fig. 1). Co-treatment of dabrafenib and afatinib, however, reversed the afatinib-mediated growth repression of the cell lines with the EGFR ex19del mutation (Fig. 1). This effect was not observed in the EGFR wild-type cell line A549, suggesting a role for the constitutively high EGFR activity and/or afatinib sensitivity in opposing the afatinib-mediated growth repression by dabrafenib. We suggest that care should be taken in developing a strategy of simultaneously inhibiting EGFR and BRAF in treating NSCLC patients. This work was supported by a grant (HI15C0554 and HI16C0286) from the Korea Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea. `Drs. Oh and Lim contributed equally.