In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 4770-4770
Abstract:
There is an urgent need to identify molecular targets that are relevant to metastatic and/or stem-like cancer cells (CSC). Theoretically, surface-expressed G-protein coupled receptors on CSC are attractive therapeutic targets. There is considerable evidence that the inflammatory milieu of the tumor microenvironment drives CSC and we now show that two isoforms of the chemokine receptor CXCR3 play important but distinct roles in cancer behavior. In the bulk tumor cell population, CXCR3, isoform A is highly expressed relative to CXCR3B. CXCR3A is critical to metastatic success. CXCR3, isoform B, is highly upregulated in breast cancer CSC. When CXCR3B is gene-silenced in a model of basal-type, metastatic breast cancer, tumorsphere-forming capacity is reduced and the aldehyde dehydrogenase-positive (ALDH1+) population is correspondingly decreased. Conversely, overexpression of CXCR3B enhances these CSC properties. Thus, CXCR3B is critical to maintenance of the phenotype and function of breast CSC. CXCR3 ligands CXCL9, CXCL10 and CXCL11 all bind with high affinity to CXCR3, however, each ligand is coupled to different intracellular signaling pathways. For example, others have reported that, in HEK cells, CXCL10 strongly induces ERK activation, but CXCL11 does not. In our hands, CXCL11 more potently induces an ALDH1+ population in MDA-MB-231 cells compared to CXCL10. We have developed novel allosteric modulators of CXCR3 that demonstrate probe (ligand)-dependence. BD64 preferentially inhibits CXCL11-mediated β-arrestin 2 recruitment relative to inhibition of GPCR signaling; BD103 is significantly more effective at blocking CXCL11 versus CXCL10-mediated GPCR signaling. Neither BD64 nor BD103 affects the proliferation of non-CSC, however both compounds inhibit the ability of CSC to form tumorspheres. Furthermore, both CXCR3 antagonists reverse ligand-mediated induction of the ALDH1+ fraction. Most interesting is that both BD64 and BD103 effectively inhibit tumor cell colonization of the lung. These data suggest that optimal tumor control will be achieved when both metastatic, CXCR3Ahigh as well as CXCR3Bhigh CSC populations are inhibited by highly specific CXCR3 modulators. Note: This abstract was not presented at the meeting. Citation Format: Namita Kundu, Regine Brox, Xinrong Ma, Jocelyn Reader, Nuska Tschammer, Amy M. Fulton. Novel CXCR3 allosteric modulators inhibit breast cancer stem cells and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4770. doi:10.1158/1538-7445.AM2017-4770
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2017-4770
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2017
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
