Schaufler, Diana, Ast, David F., Tumbrink, Hannah L., Abedpour, Nima, Maas, Lukas, Schwaebe, Ayla E., Spille, Inga, Lennartz, Stefanie, Fassunke, Jana, Aldea, Mihaela, Besse, Benjamin, Planchard, David, Nogova, Lucia, Michels, Sebastian, Kobe, Carsten, Persigehl, Thorsten, Westphal, Theresa, Koleczko, Sophia, Fischer, Rieke, Weber, Jan-Phillip, Altmueller, Janine, Thomas, Roman K., Merkelbach-Bruse, Sabine, Gautschi, Oliver, Mezquita, Laura, Buettner, Reinhard, Wolf, Juergen, Peifer, Martin, Braegelmann, Johannes, Scheffler, Matthias and Sos, Martin L. (2021). Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer. npj Precis. Oncol., 5 (1). BERLIN: NATURE PORTFOLIO. ISSN 2397-768X

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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 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Schaufler, DianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ast, David F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tumbrink, Hannah L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abedpour, NimaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maas, LukasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwaebe, Ayla E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spille, IngaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lennartz, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fassunke, JanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aldea, MihaelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Besse, BenjaminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Planchard, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nogova, LuciaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Michels, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kobe, CarstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Persigehl, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Westphal, TheresaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koleczko, SophiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, RiekeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weber, Jan-PhillipUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merkelbach-Bruse, SabineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gautschi, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mezquita, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braegelmann, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheffler, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sos, Martin L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-596726
DOI: 10.1038/s41698-021-00241-9
Journal or Publication Title: npj Precis. Oncol.
Volume: 5
Number: 1
Date: 2021
Publisher: NATURE PORTFOLIO
Place of Publication: BERLIN
ISSN: 2397-768X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DABRAFENIB PLUS TRAMETINIB; OPEN-LABEL; ACQUIRED-RESISTANCE; 1ST-LINE TREATMENT; V600E MUTATION; OSIMERTINIB; INHIBITORS; AZD9291; ADENOCARCINOMA; MULTICENTERMultiple languages
OncologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/59672

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