Basic principles of drug-induced evolutionary paths underlying BRAF-driven resistance in lung cancer patients

Overview of the biopsis and key molecular findings by NGS for patient patient 04. Flow chart (top(right) summarizes lines of therapy approches overtime after aquisition of BRAF-V600E mutation. © see Figure 1 - NPJ Precis Oncol 2021 Dec 17;5(1):102. doi: 10.1038/s41698-021-00241-9.

The identification of epidermal growth factor receptor (EGFR) mutations dramatically changed the therapeutic regimen that led to a major improvement in the overall survival of these lung cancer patients. Currently, the third-generation EGFR inhibitor osimertinib is the standard-of-care in the first-line treatment of patients with EGFR-mutant lung adenocarcinoma.  

Unfortunately, virtually all tumors develop resistance and the activation of MAPK signaling seems to play a more prominent role in patients progressive on third-generation EGFR inhibitors when compared to first- and second-generation EGFR inhibitors. BRAFV600E mutations have been identified as a resistance mechanism to osimertinib in roughly 3% of cases with EGFR-mutant lung cancer, with or without concurrent EGFRT790M mutation. Several combination therapies have been proposed to tackle these tumors, but the limited insights into the dynamics of the selection process and the cellular fitness of individual clones precludes an optimization of therapeutic regimen.

The present study describes a comprehensive and translational approach integrating the expertise from researchers from the following institutions at the Faculty of Medicine, University of Cologne and the University Hospital Cologne: Dept. I of Internal Medicine, the Center for Integrated Oncology (CIO), Institute of Pathology, Dept. of Translational Genomics and Center for Molecular Medicine Cologne. The scientists investigated the influence of mutations in the BRAF gene during therapy in patients, mouse and cellular models and uncovers basic principles of drug-induced evolutionary paths underlying BRAF-driven resistance in patients with lung adenocarcinoma. This study with the title “Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer” is published in NPJ Precis Oncol 2021 Dec 17;5(1):102. doi: 10.1038/s41698-021-00241-9.

“We were excited about the opportunity to study a cohort of 15 patients with lung adenocarcinoma and activating EGFR mutations that harbored co-occurring BRAF mutations with and without prior anti-EGFR treatment. These patients were treated with different lines of therapy and we evaluated the clonal evolution of selected patients using whole exome sequencing. In parallel, we measured the impact of BRAF-^V600E mutations on the fitness of EGFR-mutant lung cancer models during therapeutic stress”, Dr. Johannes Brägelmann, CMMC-CAP Awardee and Fellow of the Mildred Scheel School of Oncology Cologne, explains.

“Our data show that BRAF mutant cells respond to combination therapy with an EGFR inhibitor, a RAF inhibitor and a MEK inhibitor and uncover basic principles of drug-induced evolutionary paths underlying BRAF-driven resistance in patients with lung adenocarcinoma. Our data could make a direct contribution to the effective treatment of selected EGFR-mutant lung tumors that no longer respond to standard therapy”, Professor Dr. Martin Sos (Institute of Pathology, Department of Translational Genomics and Center for Molecular Medicine Cologne) comments.

Publication
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)
https://www.nature.com/articles/s41698-021-00241-9

The work was funded by the Federal Ministry of Education and Research (BMBF; e:Med), the Mildred Scheel School of Oncology and the Center for Molecular Medicine Cologne, among others.

Scientific Contact:
Prof. Dr. Martin Sos
Molekulare Pathologie, Inst. für Pathologie & Abteilung für Translationale Genomik
martin.sos[at]uni-koeln.de