TY - JOUR
T1 - CXCR4 chemokine receptor antagonists
T2 - Perspectives in SCLC
AU - Burger, Jan A.
AU - Stewart, David J.
N1 - Funding Information:
Supported by ASCO Career Development Award (to JA Burger), Kimmel Scholar Award by the Sidney Kimmel Foundation for Cancer Research (to JA Burger), and CLL Global Research Foundation grant (to JA Burger).
PY - 2009/4
Y1 - 2009/4
N2 - Small-cell lung cancer (SCLC) is a particularly aggressive form of lung cancer characterized by early and widespread metastases and the ability to rapidly develop resistance against chemotherapeutic agents. Tumor cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokine receptors and adhesion molecules. SCLC cells express high levels of CXCR4 (CD184), a seven-transmembrane G-protein-coupled chemokine receptor. Stromal cells within the bone marrow microenvironment and at extramedullary sites constitutively secrete stromal cell-derived factor-1 (CXCL12), the ligand for CXCR4. Activation of CXCR4 induces SCLC cell migration and adhesion to stromal cells that secrete CXCL12, which in turn provides growth- and drug resistance-signals to the tumor cells. CXCR4 antagonists, such as Plerixafor (AMD3100) and T140 analogues (TN14003/ BKT140), disrupt CXCR4-mediated SCLC cell-adhesion to stromal cells. In stromal cell co-cultures, CXCR4 antagonists also sensitize SCLC cells to cytotoxic drugs, such as etoposide, and thereby antagonize cell adhesion-mediated drug resistance. Therefore, targeting the CXCR4-CXCL12 axis is a novel, attractive therapeutic approach in SCLC. Here, we summarize preclinical data about CXCR4 in SCLC, and the current status of the preclinical and clinical development of CXCR4 antagonists.
AB - Small-cell lung cancer (SCLC) is a particularly aggressive form of lung cancer characterized by early and widespread metastases and the ability to rapidly develop resistance against chemotherapeutic agents. Tumor cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokine receptors and adhesion molecules. SCLC cells express high levels of CXCR4 (CD184), a seven-transmembrane G-protein-coupled chemokine receptor. Stromal cells within the bone marrow microenvironment and at extramedullary sites constitutively secrete stromal cell-derived factor-1 (CXCL12), the ligand for CXCR4. Activation of CXCR4 induces SCLC cell migration and adhesion to stromal cells that secrete CXCL12, which in turn provides growth- and drug resistance-signals to the tumor cells. CXCR4 antagonists, such as Plerixafor (AMD3100) and T140 analogues (TN14003/ BKT140), disrupt CXCR4-mediated SCLC cell-adhesion to stromal cells. In stromal cell co-cultures, CXCR4 antagonists also sensitize SCLC cells to cytotoxic drugs, such as etoposide, and thereby antagonize cell adhesion-mediated drug resistance. Therefore, targeting the CXCR4-CXCL12 axis is a novel, attractive therapeutic approach in SCLC. Here, we summarize preclinical data about CXCR4 in SCLC, and the current status of the preclinical and clinical development of CXCR4 antagonists.
KW - CXCL12
KW - CXCR4
KW - CXCR4 antagonists
KW - Tumor microenvironment
KW - Tumor stem cells
UR - http://www.scopus.com/inward/record.url?scp=67649592154&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67649592154&partnerID=8YFLogxK
U2 - 10.1517/13543780902804249
DO - 10.1517/13543780902804249
M3 - Review article
C2 - 19335276
AN - SCOPUS:67649592154
SN - 1354-3784
VL - 18
SP - 481
EP - 490
JO - Expert Opinion on Investigational Drugs
JF - Expert Opinion on Investigational Drugs
IS - 4
ER -