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EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors
Dalia Ercan1, Hwan Geun Choi2, Cai-Hong Yun3
1Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
Purpose:
Mutant selective irreversible pyrimidine-based EGFR kinase inhibitors, including WZ4002, CO-1686, and AZD9291, are effective in preclinical models and in lung cancer patients harboring the EGFR T790M gefitinib/erlotinib resistance mutation. However, little is known about how cancers develop acquired resistance to this class of EGFR inhibitors. We sought to identify and study EGFR mutations that confer resistance to this class of agents.
Experimental Design:
We performed an N-ethyl-N-nitrosourea (ENU) mutagenesis screen in EGFR-mutant (sensitizing alone or with concurrent EGFR T790M) Ba/F3 cells and selected drug-resistant clones. We evaluated the sensitivity of EGFR inhibitors in models harboring drug-resistant EGFR mutations.
Results:
We identified 3 major drug resistance mutations. EGFR L718Q, L844V, and C797S cause resistance to both WZ4002 and CO-1686 while, in contrast, only EGFR C797S leads to AZD9291 resistance. Cells containing an EGFR-sensitizing mutation, Del 19 or L858R, in conjunction with L718Q, L844V, or C797S retain sensitivity to quinazoline-based EGFR inhibitors, gefitinib and afatinib. The C797S mutation, in the presence of Del 19 or L858R and T790M, causes resistance to all current EGFR inhibitors, but L858R/T790M/C797S remains partially sensitive to cetuximab which leads to disruption of EGFR dimerization.
Conclusions:
Our findings provide insights into resistance mechanisms to irreversible pyrimidine-based EGFR inhibitors and identify specific genomic contexts in which sensitivity is retained to existing clinical EGFR inhibitors. These findings will guide the development of new strategies to inhibit EGFR.
Insights
New EGFR mutations cause resistance to targeted lung cancer drugs. Some mutations, like C797S, confer resistance to all current EGFR inhibitors, guiding future drug development.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Irreversible pyrimidine-based Epidermal Growth Factor Receptor (EGFR) kinase inhibitors (e.g., WZ4002, CO-1686, AZD9291) show efficacy against EGFR-mutant lung cancers, including those with the T790M resistance mutation.
- Acquired resistance to these advanced EGFR inhibitors is a significant clinical challenge, yet the underlying genetic mechanisms remain largely uncharacterized.
Purpose of the Study:
- To identify and characterize novel EGFR mutations that confer acquired resistance to mutant-selective, irreversible pyrimidine-based EGFR inhibitors.
- To understand the specific genomic contexts and mutation profiles associated with resistance to this class of targeted therapies.
Main Methods:
- Utilized N-ethyl-N-nitrosourea (ENU) mutagenesis screening in Ba/F3 cells engineered with EGFR mutations (sensitizing alone or with T790M).
- Selected and analyzed drug-resistant clones to identify specific EGFR mutations conferring resistance.
- Assessed the sensitivity of EGFR inhibitors in cellular models harboring the identified drug-resistant EGFR mutations.
Main Results:
- Identified three key EGFR mutations (L718Q, L844V, C797S) conferring resistance to WZ4002 and CO-1686.
- Discovered that only the EGFR C797S mutation confers resistance to AZD9291.
- Observed that EGFR-sensitizing mutations (Del 19 or L858R) combined with L718Q, L844V, or C797S retain sensitivity to older quinazoline-based inhibitors (gefitinib, afatinib).
- Found that EGFR L858R/T790M/C797S mutations confer resistance to all current EGFR inhibitors but retain partial sensitivity to cetuximab, which disrupts EGFR dimerization.
Conclusions:
- Elucidated key resistance mechanisms to irreversible pyrimidine-based EGFR inhibitors.
- Identified specific genetic profiles that maintain sensitivity to existing EGFR inhibitors, offering potential therapeutic avenues.
- Provided crucial insights for the development of next-generation EGFR inhibitors and resistance-breaking strategies in lung cancer treatment.
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