Abstract
Activation of MAPK signaling via BRAF mutations may limit the activity of EGFR inhibitors in EGFR-mutant lung cancer patients. However, the impact of BRAF mutations on the selection and fitness of emerging resistant clones during anti-EGFR therapy remains elusive. We tracked the evolution of subclonal mutations by whole-exome sequencing and performed clonal analyses of individual metastases during therapy. Complementary functional analyses of polyclonal EGFR-mutant cell pools showed a dose-dependent enrichment of BRAFV600E and a loss of EGFR inhibitor susceptibility. The clones remain stable and become vulnerable to combined EGFR, RAF, and MEK inhibition. Moreover, only osimertinib/trametinib combination treatment, but not monotherapy with either of these drugs, leads to robust tumor shrinkage in EGFR-driven xenograft models harboring BRAFV600E mutations. These data provide insights into the dynamics of clonal evolution of EGFR-mutant tumors and the therapeutic implications of BRAF co-mutations that may facilitate the development of treatment strategies to improve the prognosis of these patients.
Highlights
Targeted treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is a landmark for rational therapy addressing molecular vulnerabilities[1]
EGFR and BRAF mutations were detected at the time of initial diagnosis, whereas in ten patients, BRAF mutations were acquired after anti-EGFR therapy (Table 1)
The median duration of time elapsed from diagnosis of EGFR-mutant lung cancer to the detection of acquired BRAF mutation was 33.8 months (Fig. 1b)
Summary
Targeted treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is a landmark for rational therapy addressing molecular vulnerabilities[1]. Treatment with first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) markedly improved the clinical outcome of patients with advanced EGFR-mutant NSCLC2–5. Osimertinib is the only third-generation EGFR inhibitor approved for the sequential treatment of patients with acquired EGFRT790M resistance mutation occurring after first- and second-generation TKIs6,7. Osimertinib became the new standard-of-care in the first-line treatment of patients with EGFR-mutant NSCLC8,9. Despite the clinical efficacy of osimertinib in the first- and second-line treatment of EGFR-mutant NSCLC, drug resistance with disease progression is inevitable[10,11,12,13,14,15,16,17,18]. BRAF mutations occur in 2–4% of NSCLC patients and the vast majority are localized in the kinase domain, including the most common mutation BRAFV600E.
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