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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
Transcriptional changes associated with resistance to inhibitors of epidermal growth factor receptor revealed using
Sidra Younis1,2,3,4, Qamar Javed5, Miroslav Blumenberg6,7,8,9
1The R.O.Perelman Department of Dermatology, New York, USA. Sidra.Younis@nyumc.org.
Background:
EGFR is important in maintaining metabolic homeostasis in healthy cells, but in tumors it activates downstream signaling pathways, causing proliferation, angiogenesis, invasion and metastasis. Consequently, EGFR is targeted in cancers using reversible, irreversible or antibody inhibitors. Unfortunately, tumors develop inhibitor resistance by mutations or overexpressing EGFR, or its ligand, or activating secondary, EGFR-independent pathways.
Methods:
Here we present a global metaanalysis comparing transcriptional profiles from matched pairs of EGFR inhibitor-sensitive vs. -resistant cell lines, using 15 datasets comprising 274 microarrays. We also analyzed separately pairs of cell lines derived using reversible, irreversible or antibody inhibitors.
Results:
The metaanalysis identifies commonalities in cell lines resistant to EGFR inhibitors: in sensitive cell lines, the ontological categories involving the ErbB receptors pathways, cell adhesion and lipid metabolism are overexpressed; however, resistance to EGFR inhibitors is associated with overexpression of genes for ErbB receptors-independent oncogenic pathways, regulation of cell motility, energy metabolism, immunity especially inflammatory cytokines biosynthesis, cell cycle and responses to exogenous and endogenous stimuli. Specifically in Gefitinib-resistant cell lines, the immunity-associated genes are overexpressed, whereas in Erlotinib-resistant ones so are the mitochondrial genes and processes. Unexpectedly, lines selected using EGFR-targeting antibodies overexpress different gene ontologies from ones selected using kinase inhibitors. Specifically, they have reduced expression of genes for proliferation, chemotaxis, immunity and angiogenesis.
Conclusions:
This metaanalysis suggests that 'combination therapies' can improve cancer treatment outcomes. Potentially, use of mitochondrial blockers with Erlotinib, immunity blockers with Gefitinib, tyrosine kinase inhibitors with antibody inhibitors, may have better chance of avoiding development of resistance.
Insights
This study analyzed gene expression in EGFR inhibitor-resistant cancer cells, revealing distinct molecular pathways. Combination therapies targeting mitochondrial and immune pathways show promise for overcoming resistance.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Epidermal Growth Factor Receptor (EGFR) signaling is crucial for cellular homeostasis but drives cancer progression.
- EGFR inhibitors are standard cancer treatments, yet resistance frequently develops.
- Resistance mechanisms include EGFR mutations, overexpression, or activation of alternative signaling pathways.
Purpose of the Study:
- To compare transcriptional profiles of EGFR inhibitor-sensitive and -resistant cancer cell lines.
- To identify common and distinct molecular alterations associated with EGFR inhibitor resistance.
- To explore potential combination therapy strategies to overcome resistance.
Main Methods:
- Global meta-analysis of transcriptional profiles from 15 datasets (274 microarrays).
- Comparison of matched pairs of EGFR inhibitor-sensitive versus -resistant cell lines.
- Separate analysis of cell lines resistant to reversible, irreversible, or antibody inhibitors.
Main Results:
- EGFR inhibitor resistance is linked to overexpression of genes in ErbB-independent oncogenic pathways, cell motility, energy metabolism, immunity, and cell cycle regulation.
- Gefitinib resistance is associated with immune-associated genes, while Erlotinib resistance involves mitochondrial genes.
- EGFR antibody-resistant lines show distinct gene expression profiles compared to kinase inhibitor-resistant lines, with reduced expression of proliferation and angiogenesis genes.
Conclusions:
- EGFR inhibitor resistance involves complex alterations in cellular pathways.
- Combination therapies, such as mitochondrial or immunity blockers with specific EGFR inhibitors, may prevent or overcome resistance.
- Targeting distinct resistance mechanisms with combination therapies could improve cancer treatment outcomes.
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