CX Chemokine Receptor 7 Contributes to Survival of KRAS-Mutant Non-Small Cell Lung Cancer upon Loss of Epidermal Growth Factor Receptor
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cell Culture
2.2. Anti-Tumor Reagents
2.3. Transfection and Establishment of EGFR−/− Cell Lines
2.4. Western Blot
2.5. DNA Isolation, Polymerase Chain Reaction (PCR), and Sequencing
2.6. Colony Formation Assay
2.7. Wound Healing Assay
2.8. Cell Migration Assay
2.9. MTS Assay
2.10. Flow Cytometric Analysis
2.11. RNA Isolation and Quantitative Reverse Transcriptase PCR (qRT-PCR)
2.12. CXCR7 Knockdown Using siRNAs
2.13. EGFR Rescue in A549 EGFR−/− Cells
2.14. Patient Tumor Samples and Immunohistochemistry (IHC)
2.15. Statistical Analysis
3. Results
3.1. EGFR Knockout in A549 Cell Line
3.2. EGFR Plays a Significant Role in Cell Progression in KRAS-Dependent Lung Cancer Cells
3.3. EGFR Knockout Does Not Significantly Affect Drug Sensitivity
3.4. Effect of EGFR Loss on Downstream Pathways
3.5. CXCR7 Is Significantly Upregulated in A549 EGFR−/− Cells and EGFRwt/wt Cells Treated with EGFR Inhibitors
3.6. Dual Inhibition of CXCR7 and EGFR Downregulates MAPK (ERK1/2) and Suppresses Proliferation
3.7. Rescue of EGFR Leads to CXCR7 Downregulation in A549 EGFR−/− Cells
3.8. CXCR7 Expression, Altered by the Ablation of EGFR, Is Associated with the Genotype of NSCLC
3.9. CXCR7 Is Highly Expressed in Primary Lung Adenocarcinoma
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Combination Treatment | TKIs (µM) | CXCR7i (µM) | FA | CI | Effect |
---|---|---|---|---|---|
Afatinib + CXCR7i | 10 | 10 | 0.84 | 0.47 | Synergistic |
Erlotinib + CXCR7i | 10 | 10 | 0.55 | 0.74 | Moderately Synergistic |
Gefitinib + CXCR7i | 10 | 10 | 0.47 | >1.1 | Antagonistic |
Subtype | Strong (%) | Weak (%) | Strong-Weak (%) | Total | p-Value |
---|---|---|---|---|---|
Histology | 0.005 * | ||||
ADC | 23 (92) | 2 (8) | 0 | 25 | |
SQCC | 8 (44.5) | 6 (33.3) | 4 (22.2) | 18 | |
Other | 4 (100) | 0 | 0 | 4 |
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Liu, B.; Song, S.; Setroikromo, R.; Chen, S.; Hu, W.; Chen, D.; van der Wekken, A.J.; Melgert, B.N.; Timens, W.; van den Berg, A.; et al. CX Chemokine Receptor 7 Contributes to Survival of KRAS-Mutant Non-Small Cell Lung Cancer upon Loss of Epidermal Growth Factor Receptor. Cancers 2019, 11, 455. https://doi.org/10.3390/cancers11040455
Liu B, Song S, Setroikromo R, Chen S, Hu W, Chen D, van der Wekken AJ, Melgert BN, Timens W, van den Berg A, et al. CX Chemokine Receptor 7 Contributes to Survival of KRAS-Mutant Non-Small Cell Lung Cancer upon Loss of Epidermal Growth Factor Receptor. Cancers. 2019; 11(4):455. https://doi.org/10.3390/cancers11040455
Chicago/Turabian StyleLiu, Bin, Shanshan Song, Rita Setroikromo, Siwei Chen, Wenteng Hu, Deng Chen, Anthonie J. van der Wekken, Barbro N. Melgert, Wim Timens, Anke van den Berg, and et al. 2019. "CX Chemokine Receptor 7 Contributes to Survival of KRAS-Mutant Non-Small Cell Lung Cancer upon Loss of Epidermal Growth Factor Receptor" Cancers 11, no. 4: 455. https://doi.org/10.3390/cancers11040455