CXCL12 (SDF1alpha)-CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies?

Abstract

Addition of multiple molecularly targeted agents to the existing armamentarium of chemotherapeutics and radiotherapies represents a significant advance in the management of several advanced cancers. In certain tumor types with no efficacious therapy options, these agents have become the first line of therapy, for example, sorafenib in advanced hepatocellular carcinoma or bevacizumab in recurrent glioblastoma. Unfortunately, in many cases, the survival benefits are modest, lasting only weeks to a few months. Moreover, they may not show benefit in patients with localized disease (i.e., in the adjuvant setting). Recent studies have provided increasing evidence that activation of the chemokine CXCL12 (SDF1α) pathway is a potential mechanism of tumor resistance to both conventional therapies and biological agents via multiple complementary actions: (i) by directly promoting cancer cell survival, invasion, and the cancer stem and/or tumor-initiating cell phenotype; (ii) by recruiting "distal stroma" (i.e., myeloid bone marrow-derived cells) to indirectly facilitate tumor recurrence and metastasis; and (iii) by promoting angiogenesis directly or in a paracrine manner. Here, we discuss recent preclinical and clinical data that support the potential use of anti-CXCL12 agents (e.g., AMD3100, NOX-A12, or CCX2066) as sensitizers to currently available therapies by targeting the CXCL12/CXCR4 and CXCL12/CXCR7 pathways.

Figure 1. CXCL12 pathway

CXCL12 binds to CXCR4 and CXCR7, which are G protein-coupled receptors (GPCR) that can form homodimers or heterodimers. In the latter case, CXCR7 changes the conformation of the CXCR4/G-protein complexes and abrogates signaling. Activation of CXCR4 by CXCL12 leads to G-protein coupled signaling through PI3K/Akt, IP3, and MAPK pathways, which promote cell survival, proliferation and chemotaxis. In addition, the β-arrestin pathway can be activated through GRK to internalize CXCR4. When CXCR7 binds CXCL12, the classical GPCR mobilization of Ca²⁺ does not occur, and activation of the β-arrestin pathway may lead to scavenging of CXCL12. In certain cancer cells (e.g., glioma) CXCR7 can also signal through PLC/MAPK to increase cell survival.