Targeting CXCR2 Enhances Chemotherapeutic Response, Inhibits Mammary Tumor Growth, Angiogenesis, and Lung Metastasis

Abstract

Breast cancer is one of the leading causes of cancer deaths among females. Many challenges exist in the current management of advanced stage breast cancer as there are fewer recognized therapeutic strategies, often due to therapy resistance. How breast cancer cells evade chemotherapy and the underlying mechanism remains unclear. We and others have observed that malignant cells that survive initial chemo-and radiation therapy express higher levels of CXCR2 ligands which might provide a survival benefit leading to therapy resistance. In this report, we test the hypothesis that CXCR2-dependent signaling in malignant cells might be critical for chemotherapy resistance and targeting this signaling axis may enhance the antitumor and antimetastatic activity of chemotherapeutic drugs and limit their toxicity. We used Cl66-wt, 4T1-wt, Cl66sh-CXCR2 and 4T1sh-CXCR2 cells expressing differential levels of the CXCR2 receptor to evaluate the role of targeting CXCR2 on chemotherapeutic responses. Knockdown of CXCR2 enhances paclitaxel and doxorubicin mediated toxicity at suboptimal doses. Moreover, we observed an increase in the expression of CXCL1, a CXCR2 ligand in paclitaxel and doxorubicin treated mammary tumor cells which were inhibited following CXCR2 knockdown. Knockdown of CXCR2 enhanced antitumor activity of paclitaxel in an in vivo mammary tumor model. We observed significant inhibition of spontaneous lung metastases in animals bearing CXCR2 knockdown tumors and treated with paclitaxel as compared to the control group. Our data suggest the novel role of CXCR2 and its ligands in maintaining chemotherapy resistance and provide evidence that targeting CXCR2-signaling in an adjuvant setting will help circumvent chemotherapy resistance.

IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells

“…The IL8-CXCR2 pathway has been shown to be important in the pathogenesis of solid tumors, and preclinical studies have demonstrated a role for this pathway in the breast cancer microenvironment. 22,27,28,30,45 Various small molecule CXCR2 inhibitors are being developed clinically, and one is being tested in a clinical trial in breast cancer. Our results demonstrate that this pathway is also functionally important for the viability of leukemic stem cell compartments in AML and MDS.…”

“…IL8 is a known potent proinflammatory cytokine that exerts its effects through binding to its G protein-coupled receptors CXCR1 and CXCR2. Extensive work in solid tumors has shown that IL8 is critical in survival, invasion, and proliferation of cancer cells [21][22][23][24] and might be an important regulator of cancer stem cell activity. [25][26][27] Activation of multiple pathways by IL8, including phosphatidylinositol 3-kinase/protein kinase B (AKT), phospholipase C/protein kinase C, and mitogen-activated protein kinase (MAPK) signaling, leads to increased expression of various The online version of this article contains a data supplement.…”

CXCL1 promotes tumor growth through VEGF pathway activation and is associated with inferior survival in gastric cancer

“…chemotherapy against breast tumors and particularly against metastatic activity [40]. Knockdown of CXCR2 was also found to enhance the antitumor activity of paclitaxel in an in vivo mammary tumor model [41]. Anti-VEGF therapy is in clinical use for the treatment of GC [42,43].…”

Potent and Efficacious Inhibition of CXCR2 Signaling by Biparatopic Nanobodies Combining Two Distinct Modes of Action

“…The chemokine receptor CXCR2 is considered a key molecular target for the diagnosis and treatment of a variety of acute and chronic inflammatory diseases such as chronic obstructive pulmonary disease, asthma, fibrosis, psoriasis, multiple sclerosis, cystic fibrosis, rheumatoid arthritis, inflammatory bowel disease, allograft rejection, and angiogenesis and also in cancer metastasis (Stadtmann and Zarbock, 2012;Hertzer et al, 2013;Sharma et al, 2013). CXCR2 is a G proteincoupled receptor (GPCR) that is expressed on many different cells and tissues, including neutrophils, mast cells, CD8…”