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Cancers 2019, 11(4), 455; https://doi.org/10.3390/cancers11040455

CX Chemokine Receptor 7 Contributes to Survival of KRAS-Mutant Non-Small Cell Lung Cancer upon Loss of Epidermal Growth Factor Receptor

1
Groningen Research Institute of Pharmacy, Department of Chemical and Pharmaceutical Biology, University of Groningen, 9713 AV Groningen, The Netherlands
2
Toxicology and Targeting Groningen Research Institute for Pharmacy, Department of Pharmacokinetics, University of Groningen, 9713 AV Groningen, The Netherlands
3
Department of Thoracic Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, China
4
Department of Pulmonary Diseases, University Medical Centre Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
5
GRIAC- Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
6
Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
*
Author to whom correspondence should be addressed.
Received: 14 February 2019 / Revised: 25 March 2019 / Accepted: 27 March 2019 / Published: 30 March 2019
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Abstract

KRAS-driven non-small cell lung cancer (NSCLC) patients have no effective targeted treatment. In this study, we aimed to investigate targeting epidermal growth factor receptor (EGFR) as a therapeutic approach in KRAS-driven lung cancer cells. We show that ablation of EGFR significantly suppressed tumor growth in KRAS-dependent cells and induced significantly higher expression of CX chemokine receptor 7 (CXCR7) and activation of MAPK (ERK1/2). Conversely, rescue of EGFR led to CXCR7 downregulation in EGFR−/− cells. Dual EGFR and CXCR7 inhibition led to substantial reduction of MAPK (pERK) and synergistic inhibition of cell growth. Analysis of two additional EGFR knockout NSCLC cell lines using CRISPR/Cas9 revealed genotype dependency of CXCR7 expression. In addition, treatment of different cells with gefitinib increased CXCR7 expression in EGFRwt but decreased it in EGFRmut cells. CXCR7 protein expression was detected in all NSCLC patient samples, with higher levels in adenocarcinoma as compared to squamous cell lung carcinoma and healthy control cases. In conclusion, EGFR and CXCR7 have a crucial interaction in NSCLC, and dual inhibition may be a potential therapeutic option for NSCLC patients. View Full-Text
Keywords: epidermal growth factor receptor (EGFR); CXCR7; KRAS; lung cancer; targeted therapy; gene editing epidermal growth factor receptor (EGFR); CXCR7; KRAS; lung cancer; targeted therapy; gene editing
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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.; Saber, A.; Haisma, H.J. 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.

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