Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer.
Diana SchauflerDavid F AstHannah L TumbrinkNima AbedpourLukas MaasAyla E SchwäbeInga SpilleStefanie LennartzJana FassunkeMihaela AldeaBenjamin BesseDavid PlanchardLucia NogovaSebastian MichelsCarsten KobeThorsten PersigehlTheresa WestphalSophia KoleczkoRieke FischerJan-Phillip WeberJanine AltmüllerRoman K ThomasSabine Merkelbach-BruseOliver GautschiLaura MezquitaReinhard ButtnerJürgen WolfMartin PeiferJohannes BrägelmannMatthias SchefflerMartin L SosPublished in: NPJ precision oncology (2021)
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 BRAF V600E 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 BRAF V600E 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.
Keyphrases
- small cell lung cancer
- epidermal growth factor receptor
- tyrosine kinase
- wild type
- end stage renal disease
- advanced non small cell lung cancer
- chronic kidney disease
- newly diagnosed
- metastatic colorectal cancer
- ejection fraction
- stem cells
- machine learning
- prognostic factors
- randomized controlled trial
- clinical trial
- physical activity
- peritoneal dialysis
- oxidative stress
- single cell
- signaling pathway
- mesenchymal stem cells
- artificial intelligence
- combination therapy
- double blind
- patient reported