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

Abstract

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.

Aberrant CXCR4 Signaling at Crossroad of WHIM Syndrome and Waldenstrom’s Macroglobulinemia

“…These somatic mutations are primarily subclonal, and almost always associated with the MYD88 L265P mutation, the first identified recurring mutation in almost 67-90% of non-IgM secreting WM patients [6]. All 17 CXCR4 heterozygous mutations identified so far in WM span in the C-ter of the receptor, and closely resemble the already documented germline mutations of CXCR4 C-ter occurring in heterozygosis in WHIM syndrome [9]. Although their relevance for clinical presentation and overall survival, as well as their relationship with resistance to chemotherapy are still unsolved issues [26][27][28], several studies reported that patients with CXCR4 mutations present a significantly lower rate of adenopathy, and those with CXCR4 nonsense mutations have an increased BM disease burden, serum IgM levels, and/or risk of symptomatic hyperviscosity [29].…”

“…At least 20 different WHIM/WHIM-like mutations have been described so far in the genomic region of chromosome 2q21 that encodes the C-ter of CXCR4 [9,29] (Figure 1). Interestingly, these mutations occur in the context of a gene that is highly conserved across species and span in a genomic region that is even more highly conserved than the gene as a whole [32].…”

“…Acquired CXCR4 WHIM-like mutations, are present in up to 40% of patients with WM and are nearly always observed in conjunction with the MYD88 L265P mutation [29]. CXCR4 mutations are essentially unique to WM, as they have not been described so far in other malignancies, except for several cases of patients affected by follicular lymphoma [9,22]. Among the different CXCR4 mutations observed, 5 are NS and 12 FS [34].…”

“…Since CXCR4 is an attractive target for diverse diseases and is considered as one of the best potential targets in hematological tumors, several efforts are currently ongoing aimed at developing specific inhibitors including small molecules, peptides, antibodies, and siRNA that abrogate receptor activity [8]. Of note, several clinical trials proposed CXCR4 inhibitors for treatment of hematological tumors alone or in combination with chemotherapy or biological agents [9]. Although the CXCR4 antagonist Plerixafor (also known as AMD3100) is an Food and Drug Administration (FDA)-approved drug and represents a valid therapeutic approach in both WHIM and WM, the complexity of its use in clinical practice indicates the need to develop new strategies.…”

“…Although the CXCR4 antagonist Plerixafor (also known as AMD3100) is an Food and Drug Administration (FDA)-approved drug and represents a valid therapeutic approach in both WHIM and WM, the complexity of its use in clinical practice indicates the need to develop new strategies. Other CXCR4 antagonists such as Mavorixafor (also known as AMD11070) the humanized IgG blocking monoclonal antibody BMS-936564 (also known as Ulocuplumab) are currently tested in clinical trials for WHIM and WM and showed promising results [9]. Targeting the other part of the axis, CXCL12, also represents an attractive alternative approach that may facilitate regulation rather than the abrogation of receptor activity, although the extremely high evolutionary conservation of this chemokine gets the generation of efficacious antibodies complicated.…”