Title |
Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors
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Published in |
Clinical Cancer Research, October 2016
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DOI | 10.1158/1078-0432.ccr-15-1915 |
Pubmed ID | |
Authors |
Sandra Ortiz-Cuaran, Matthias Scheffler, Dennis Plenker, llona Dahmen, Andreas H. Scheel, Lynnette Fernandez-Cuesta, Lydia Meder, Christine M. Lovly, Thorsten Persigehl, Sabine Merkelbach-Bruse, Marc Bos, Sebastian Michels, Rieke Fischer, Kerstin Albus, Katharina König, Hans-Ulrich Schildhaus, Jana Fassunke, Michaela A. Ihle, Helen Pasternack, Carina Heydt, Christian Becker, Janine Altmüller, Hongbin Ji, Christian Müller, Alexandra Florin, Johannes M. Heuckmann, Peter Nuernberg, Sascha Ansén, Lukas C. Heukamp, Johannes Berg, William Pao, Martin Peifer, Reinhard Buettner, Jürgen Wolf, Roman K. Thomas, Martin L. Sos |
Abstract |
To identify novel mechanisms of resistance to third-generation EGFR inhibitors in lung adenocarcinoma patients that progressed under therapy with either AZD9291 or rociletinib (CO-1686). We analyzed tumor biopsies from seven patients obtained before, during and/or after treatment with AZD9291or rociletinib (CO-1686). Targeted sequencing and FISH analyses were performed and the relevance of candidate genes was functionally assessed in in vitro models. We found recurrent amplification of either MET or ERBB2 in tumors that were resistant or developed resistance to third-generation EGFR inhibitors and show that ERBB2 and MET activation can confer resistance to these compounds. Furthermore, we identified a KRASG12S mutation in a patient with acquired resistance to AZD9291 as a potential driver of acquired resistance. Finally, we show that dual inhibition of EGFR/MEK might be a viable strategy to overcome resistance in EGFR-mutant cells expressing mutant KRAS. Our data suggests that heterogeneous mechanisms of resistance can drive primary and acquired resistance to third-generation EGFR inhibitors and provides a rationale for potential combination strategies. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 3 | 20% |
France | 2 | 13% |
Montenegro | 1 | 7% |
Spain | 1 | 7% |
Venezuela, Bolivarian Republic of | 1 | 7% |
United Kingdom | 1 | 7% |
Germany | 1 | 7% |
Unknown | 5 | 33% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Scientists | 6 | 40% |
Members of the public | 6 | 40% |
Practitioners (doctors, other healthcare professionals) | 3 | 20% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 1 | <1% |
Unknown | 127 | 99% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 31 | 24% |
Student > Ph. D. Student | 17 | 13% |
Student > Master | 14 | 11% |
Other | 12 | 9% |
Student > Bachelor | 10 | 8% |
Other | 15 | 12% |
Unknown | 29 | 23% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 27 | 21% |
Biochemistry, Genetics and Molecular Biology | 27 | 21% |
Agricultural and Biological Sciences | 21 | 16% |
Pharmacology, Toxicology and Pharmaceutical Science | 6 | 5% |
Chemistry | 4 | 3% |
Other | 8 | 6% |
Unknown | 35 | 27% |