CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC

Becker, Jeffrey H.; Gao, Yandi; Soucheray, Margaret; Pulido, Inés; Kikuchi, Eiki; Rodriguez, María L.; Gandhi, Rutu; Lafuente-Sanchis, Aranzazu; Aupí, Miguel; Fernández-Coronado, Javier Alcácer; Martín-Martorell, Paloma; Cremades, Antonio; Galbis-Caravajal, José M.; Alcácer, Javier; Christensen, Camilla L.; Simms, Patricia; Hess, Ashley; Asahina, Hajime; Kahle, Michael; Al‐Shahrour, Fátima; Borgia, Jeffrey A.; Lahoz, Agustín; Insa, Amelia; Juan, Óscar; Jänne, Pasi A.; Wong, Kwok-Kin; Carretero, Julián; Shimamura, Takeshi

doi:10.1158/0008-5472.can-19-0024

Cited by 51 publications

(39 citation statements)

References 64 publications

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“…Recently, it has been found that when KRAS-driven non-small cell lung cancer (NSCLC) patients were treated with epidermal growth factor receptor (EGFR) targeting therapeutic approach, significantly higher expression of CXCR7 were observed and MAPK (ERK1/2) signaling was activated, implying that EGFR and CXCR7 had a crucial interaction in NSCLC [ 37 ]. Furthermore, Becker JH et al considered that CXCR7 inhibition could prevent the emergence of acquired EGFR tyrosine kinase inhibitor (TKI) resistance in EGFR mutant NSCLC with an EMT phenotype [ 38 ]. In this study, we systematically investigate the role of CXCR7 independent of CXCR4 in lung tumor growth and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of CXCR7 accelerates tumor growth and metastasis of lung cancer cells

Liu

Qian

et al. 2020

Respir Res

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Background Under physiological conditions, CXCL12 modulates cell proliferation, survival, angiogenesis, and migration mainly through CXCR4. Interestingly, the newly discovered receptor CXCR7 for CXCL12 is highly expressed in many tumor cells as well as tumor-associated blood vessels, although the level of CXCR7 in normal cells is low. Recently, many studies have suggested that CXCR7 promotes cell growth and metastasis in more than 20 human malignancies, among which lung cancer is the leading cause of cancer-associated deaths worldwide. Thus, the mechanism of CXCR7 in the progression of lung cancer is urgently needed. Methods First, we explored CXCR4 and CXCR7 expression in human lung cancer specimens and cell lines by immunohistochemistry, western blot and flow cytometry. Then, we chose the human lung adenocarcinoma cell line A549 that stably overexpressed CXCR7 through the way of lentivirus-mediated transduction. Next, “wound healing” assay and transwell assay were applied to compare the cell migration and invasion ability, and stripe assay was used to evaluate the cell polarization. Last, our team established a mouse xenograft model of human lung cancer and monitored tumor proliferation and metastasis by firefly luciferase bioluminescence imaging in SCID/Beige mice. Results In clinical lung cancer samples, CXCR7 expression was almost not detected in normal tissue but upregulated in lung tumor tissue, whereas, CXCR4 was highly expressed in both normal and tumor tissues. Furthermore, overexpression of CXCR7 enhanced A549 cell migration and polarization in vitro. Besides, mouse xenograft model of human lung cancer showed that CXCR7 promoted primary lung tumor’s growth and metastasis to the second organ, such as liver or bone marrow in SCID/Beige mice in vivo. Conclusions This study describes the multiple functions of CXCR7 in lung cancer. Thus, these results suggest that CXCR7 may be a malignancy marker and may provide a novel target for anticancer therapy.

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Section: Discussionmentioning

confidence: 99%

Overexpression of CXCR7 accelerates tumor growth and metastasis of lung cancer cells

Liu

Qian

et al. 2020

Respir Res

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“…CXCR7 could also heterodimerize with Epidermal Growth Factor Receptor (EGFR) [ 46 , 47 ] to activate MAPK pathways [ 48 ]; however, the activation of the MAPK signaling by CXCR7 occurs in conditioning of EGFR inhibition with tyrosine kinase inhibitors (TKIs). CXCR7 promotes resistance to the TKI osimertinib in non-small-cell lung cancer (NSCLC) [ 49 ]. CXCR7 overexpression has recently been linked to acquired enzalutamide resistance in prostate cancer [ 50 ].…”

Section: Cxcl12/cxcr4 Axis In Tumorsmentioning

confidence: 99%

“…CXCR7 overexpression has recently been linked to acquired enzalutamide resistance in prostate cancer [ 50 ]. CXCR7 is ubiquitously overexpressed in acquired EGFR TKI resistant cell line NSCLC models with an epithelial–mesenchymal transition (EMT) phenotype [ 49 ]. While CXCR4 is known to promote EMT, the depletion of CXCR7 alone is sufficient to reverse the EMT phenotype in lung cancer models [ 49 ].…”

Section: Cxcl12/cxcr4 Axis In Tumorsmentioning

confidence: 99%

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

et al. 2020

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Deciphering the molecular alterations leading to disease initiation and progression is currently crucial to identify the most relevant targets for precision therapy in cancer patients. Cancers express a complex chemokine network influencing leucocyte infiltration and angiogenesis. Moreover, malignant cells also express a selective repertoire of chemokine receptors that sustain their growth and spread. At present, different cancer types have been shown to overexpress C-X-C chemokine receptor type 4 (CXCR4) and to respond to its ligand C-X-C motif chemokine 12 (CXCL12). The CXCL12/CXCR4 axis influences cancer biology, promoting survival, proliferation, and angiogenesis, and plays a pivotal role in directing migration of cancer cells to sites of metastases, making it a prognostic marker and a therapeutic target. More recently, mutations in the C-terminus of CXCR4 have been identified in the genomic landscape of patients affected by Waldenstrom’s macroglobulinemia, a rare B cell neoplasm. These mutations closely resemble those occurring in Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis (WHIM) syndrome, an immunodeficiency associated with CXCR4 aberrant expression and activity and with chemotherapy resistance in clinical trials. In this review, we summarize the current knowledge on the relevance of CXCR4 mutations in cancer biology, focusing on its importance as predictors of clinical presentation and response to therapy.

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“…Recently, it has been found that when KRAS-driven non-small cell lung cancer (NSCLC) patients were treated with epidermal growth factor receptor (EGFR) targeting therapeutic approach, significantly higher expression of CXCR7 were observed and MAPK (ERK1/2) signaling was activated, implying that EGFR and CXCR7 had a crucial interaction in NSCLC [37]. Furthermore, Becker JH et al considered that CXCR7 inhibition could prevent the emergence of acquired EGFR tyrosine kinase inhibitor (TKI) resistance in EGFR mutant NSCLC with an EMT phenotype [38]. Thus it can be concluded that CXCR7 expression is strictly regulated during pathological processes especially in malignancies, which might relate to their augmented growth and migrate capacities and in line with an advantage for metastasis.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of CXCR7 Enhances Metastasis on Lung Cancer Cell

Liu

Qian²,

sheng

et al. 2020

Preprint

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Background Under physiological conditions, CXCL12 modulates cell proliferation, survival, angiogenesis, and migration mainly through CXCR4. Interestingly, the newly discovered receptor CXCR7 for CXCL12 is highly expressed in many tumor cells as well as tumor-associated blood vessels, although the level of CXCR7 in normal cells is low. Recently, many studies have suggested that CXCR7 promotes cell growth and metastasis in more than 20 human malignancies, among which lung cancer is the leading cause of cancer-associated deaths worldwide. Thus, the mechanism of CXCR7 in the progression of lung cancer is urgently needed. Methods First, we explored CXCR4 and CXCR7 expression in human lung cancer specimens and cell lines by immunohistochemistry, western blot and flow cytometry. Then, we chose the human lung adenocarcinoma cell line A549 that stably overexpressed CXCR7 through the way of lentivirus-mediated transduction. Next, “wound healing” assay and transwell assay were applied to compare the cell migration and invasion ability, and stripe assay was used to evaluate the cell polarization. Last, our team established a mouse xenograft model of human lung cancer and monitored tumor proliferation and metastasis by firefly luciferase bioluminescence imaging in SCID/Beige mice. Results In clinical lung cancer samples, CXCR7 were highly expressed in lung tumor tissue compared with normal tissue, and, CXCR4 highly expressed in both normal and tumor tissues. Furthermore, overexpression of CXCR7 enhanced A549 cell migration and polarization in vitro. Besides, mouse xenograft model of human lung cancer showed that CXCR7 promoted primary lung tumor’s growth and metastasis to the second organ, such as liver or bone marrow in SCID/Beige mice in vivo. Conclusions This study describes the multiple functions of CXCR7 in lung cancer. Thus, these results suggest that CXCR7 may be a malignancy marker and may provide a novel target for anticancer therapy.

show abstract

CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC

Cited by 51 publications

References 64 publications

Overexpression of CXCR7 accelerates tumor growth and metastasis of lung cancer cells

Overexpression of CXCR7 accelerates tumor growth and metastasis of lung cancer cells

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

Overexpression of CXCR7 Enhances Metastasis on Lung Cancer Cell

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