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Host-Dependent Phenotypic Resistance to EGFR Tyrosine Kinase Inhibitors
Yuya Haga1,2, Ilaria Marrocco1, Ashish Noronha1
1Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
Abstract:
Lung cancers driven by mutant forms of EGFR invariably develop resistance to kinase inhibitors, often due to secondary mutations. Here we describe an unconventional mechanism of resistance to dacomitinib, a newly approved covalent EGFR kinase inhibitor, and uncover a previously unknown step of resistance acquisition. Dacomitinib-resistant (DR) derivatives of lung cancer cells were established by means of gradually increasing dacomitinib concentrations. These DR cells acquired no secondary mutations in the kinase or other domains of EGFR. Along with resistance to other EGFR inhibitors, DR cells acquired features characteristic to epithelial-mesenchymal transition, including an expanded population of aldehyde dehydrogenase-positive cells and upregulation of AXL, a receptor previously implicated in drug resistance. Unexpectedly, when implanted in animals, DR cells reverted to a dacomitinib-sensitive state. Nevertheless, cell lines derived from regressing tumors displayed renewed resistance when cultured in vitro. Three-dimensional and cocultures along with additional analyses indicated lack of involvement of hypoxia, fibroblasts, and immune cells in phenotype reversal, implying that other host-dependent mechanisms might nullify nonmutational modes of resistance. Thus, similar to the phenotypic resistance of bacteria treated with antibiotics, the reversible resisters described here likely evolve from drug-tolerant persisters and give rise to the irreversible, secondary mutation-driven nonreversible resister state. SIGNIFICANCE: This study reports that stepwise acquisition of kinase inhibitor resistance in lung cancers driven by mutant EGFR comprises a nonmutational, reversible resister state. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/14/3862/F1.large.jpg.
Insights
Lung cancer cells developed reversible resistance to dacomitinib without secondary mutations. This nonmutational resistance, similar to persister cells, can evolve into irreversible, mutation-driven resistance.
Area of Science:
- Oncology
- Molecular Biology
- Drug Resistance
Background:
- Epidermal growth factor receptor (EGFR) mutations drive lung cancer, but resistance to targeted therapies like kinase inhibitors is common.
- Secondary mutations in EGFR are a primary mechanism of acquired resistance to EGFR inhibitors.
- Dacomitinib is a covalent EGFR kinase inhibitor used to treat certain types of lung cancer.
Purpose of the Study:
- To investigate unconventional mechanisms of dacomitinib resistance in EGFR-mutant lung cancer.
- To identify and characterize a novel, nonmutational step in the acquisition of drug resistance.
- To explore the reversibility of this resistance phenotype and its implications for treatment.
Main Methods:
- Established dacomitinib-resistant (DR) lung cancer cell lines by gradually increasing drug concentrations.
- Analyzed DR cells for secondary mutations in EGFR and assessed resistance to other EGFR inhibitors.
- Investigated phenotypic changes, including epithelial-mesenchymal transition (EMT) markers and aldehyde dehydrogenase (ALDH) activity.
- Evaluated the reversibility of resistance by implanting DR cells in animal models and re-culturing derived cell lines.
- Conducted 3D and co-culture experiments to explore potential host-dependent resistance reversal mechanisms.
Main Results:
- Dacomitinib-resistant cells acquired resistance without secondary EGFR mutations.
- DR cells exhibited features of epithelial-mesenchymal transition and increased AXL expression, a marker of drug resistance.
- Implantation into animals led to a reversible loss of dacomitinib resistance.
- Cell lines derived from regressing tumors re-acquired resistance upon in vitro culture.
- Host-dependent mechanisms, not hypoxia, fibroblasts, or immune cells, were implicated in phenotype reversal.
Conclusions:
- EGFR-mutant lung cancers can acquire a nonmutational, reversible state of resistance to kinase inhibitors like dacomitinib.
- This reversible resistance may arise from drug-tolerant persister cells, preceding the development of irreversible, mutation-driven resistance.
- Understanding this reversible resistance is crucial for developing strategies to overcome or prevent acquired drug resistance in lung cancer.
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