Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors.

Clin Cancer Res 2016 Oct 1;22(19):4837-4847. Epub 2016 Jun 1.

Molecular Pathology, Center of Integrated Oncology, University Hospital Cologne, Cologne, Germany.

Purpose: To identify novel mechanisms of resistance to third-generation EGFR inhibitors in patients with lung adenocarcinoma that progressed under therapy with either AZD9291 or rociletinib (CO-1686).

Experimental Design: We analyzed tumor biopsies from seven patients obtained before, during, and/or after treatment with AZD9291 or rociletinib (CO-1686). Targeted sequencing and FISH analyses were performed, and the relevance of candidate genes was functionally assessed in in vitro models.

Results: 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 KRAS 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 CONCLUSIONS: Our data suggest that heterogeneous mechanisms of resistance can drive primary and acquired resistance to third-generation EGFR inhibitors and provide a rationale for potential combination strategies. Clin Cancer Res; 22(19); 4837-47. ©2016 AACR.

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-15-1915DOI Listing
October 2016
79 Reads

Publication Analysis

Top Keywords

resistance third-generation
16
egfr inhibitors
16
acquired resistance
16
third-generation egfr
16
resistance
9
mechanisms resistance
8
azd9291 rociletinib
8
heterogeneous mechanisms
8
primary acquired
8
compounds identified
4
identified kras
4
resistance compounds
4
confer resistance
4
activation confer
4
kras mutation
4
mutation patient
4
azd9291 potential
4
resistance finally
4
met activation
4
resistance azd9291
4

Similar Publications