Publication in NPJ Precision Oncology


Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer

a Spectrum and distribution of BRAF co-mutations in patients with EGFR-mutant lung adenocarcinoma. b Kaplan–Meier curve of the time elapsed from the detection of the EGFR mutation until the detection of the acquired BRAF mutation (as events) in days. c Kaplan–Meier curve of overall survival for patients P01, P04, P12–P15 that were available for survival analysis. d Overview of the biopsies and key molecular findings by NGS for patient P04. Flow chart (top right) summarizes lines of therapy approaches overtime after the acquisition of BRAFV600E mutation. e, f Clustering of WES-derived mutations based on their CCFs between pairs of tumor biopsies to detect clusters of shared clonal and private mutations. Candidate mutations in EGFR and BRAF are highlighted. g Subclonal composition in individual biopsies indicating two subclones (C1, C3) in the peritoneal metastasis and single clones in the liver metastases. h Clonal evolution of reconstructed cell populations presented as a phylogenetic tree. The computationally inferred most common ancestor C0 is common to all subsequent clones and highlighted mutations are present in descendent clones. (i) Visualization of evolutionary genetic distances between normal tissue and longitudinal biopsies. WES whole-exome sequencing, NGS next-generation sequencing, PD progressive disease, PR partial response, D + T dabrafenib+trametinib, O + D( + T) osimertinib+dabrafenib(+trametinib), O + CTX + B osimertinib+chemotherapy+bevacizumab, O + Tc TACE osimertinib+transarterial chemoembolization, C clone, CCF cancer cell fraction.

Targeted therapy is first-line therapy for lung tumors with EGFR mutations. The success of the therapy is limited, however. This is due to further mutations, or the activation of other signaling pathways in the cancer cells. Through the collaboration of the Dept. I of Internal Medicine (CIO) and the Molecular Pathology (Institute of Pathology, Dept. of Translational Genomics and Center for Molecular Medicine Cologne) we were able to investigate the influence of mutations in the BRAF gene during therapy in patients, mouse and cellular models. Our data show that BRAF mutant cells respond to combination therapy with an EGFR inhibitor, a RAF inhibitor and a MEK inhibitor. These data could make a direct contribution to the effective treatment of EGFR-mutated lung tumors that no longer respond to standard therapy. The work was funded by the Federal Ministry of Education and Research (BMBF; e:Med) and the Mildred Scheel School of Oncology, among others.


Reference: Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer. Schaufler D*, Ast DF*, Tumbrink HL, Abedpour N, Maas L, Schwäbe AE, Spille I, Lennartz S, Fassunke J, Aldea M, Besse B, Planchard D, Nogova L, Michels S, Kobe C, Persigehl T, Westphal T, Koleczko S, Fischer R, Weber JP, Altmüller J, Thomas RK, Merkelbach-Bruse S, Gautschi O, Mezquita L, Büttner R, Wolf J, Peifer M, Brägelmann J§, Scheffler M§, Sos ML§. NPJ Precis Oncol 2021 Dec 17;5(1):102. doi: 10.1038/s41698-021-00241-9. (*=authors contributed equally; §=shared correspondence)