Abstract: Maraviroc (UK-427857) is a potent, orally bioavailable small-molecule antagonist of the C-C chemokine receptor type 5 (CCR5), originally developed and approved for the treatment of HIV-1 infection. Recently, its therapeutic potential has expanded significantly into the field of oncology. Tumor cells frequently hijack the CCL5/CCR5 chemokine axis to promote tumor growth, direct metastasis, expand cancer stem cell populations, and establish an immunosuppressive tumor microenvironment. This comprehensive literature review explores the repurposing of maraviroc in oncology, detailing its pharmacological activity across various solid and hematological malignancies, its molecular mechanisms of action, and its structure-activity relationship. Furthermore, the review discusses current limitations in its clinical application and highlights future perspectives, particularly its promising role in combination with immune checkpoint inhibitors and DNA-damaging chemotherapies.
1. Introduction
Maraviroc (UK-427857) is a selective, orally bioavailable small-molecule inhibitor of the C-C chemokine receptor type 5 (CCR5) [2]. It was initially discovered and optimized as a host-targeted antiretroviral drug to prevent the entry of CCR5-tropic (R5) human immunodeficiency virus type 1 (HIV-1) into CD4+ cells, becoming the first drug of its class approved for clinical use [2]. In recent years, the focus on maraviroc has shifted toward oncology. The CCL5/CCR5 axis is now recognized as a critical pathway hijacked by cancer cells to support tumor progression, metastasis, and immune evasion [1]. Abnormal expression and activity of CCL5 and CCR5 have been documented in numerous malignancies, including breast cancer, colorectal cancer, pancreatic cancer, prostate cancer, and hematological tumors like Hodgkin lymphoma [1][3]. Consequently, maraviroc is being extensively investigated as a repurposed therapeutic agent to dismantle the tumor-promoting microenvironment and halt cancer progression [1][8].
2. Pharmacological Activity
In the context of oncology, maraviroc exhibits broad pharmacological activity by targeting both the cancer cells directly and the surrounding tumor microenvironment (TME).
Tumor Growth and Metastasis: Maraviroc has demonstrated significant efficacy in reducing tumor growth and metastatic burden in preclinical models. In breast cancer, it blocks cellular metastasis, inhibits angiogenesis, and reduces lung metastasis [1][3]. In colorectal cancer (CRC), maraviroc decreases the accumulation of cancer-associated fibroblasts (CAFs) and reduces orthotopic tumor xenograft growth [1]. It also inhibits the proliferation and invasion of pancreatic ductal adenocarcinoma (PDAC) cells, leading to a reduction in liver metastases [1]. Furthermore, in prostate cancer models, maraviroc combined with autophagy inhibitors has been shown to reduce metastasis and improve overall survival [1].
Immune Modulation: A major pharmacological effect of maraviroc is its ability to reverse tumor-induced immunosuppression. It repolarizes tumor-associated macrophages (TAMs) from a pro-tumorigenic, immunosuppressive M2-like state toward an anti-tumoral M1-like state, a phenomenon observed in CRC and glioblastoma models [1][4]. Additionally, maraviroc decreases the recruitment of regulatory T cells (Tregs) and monocytes to the tumor site, thereby alleviating the suppression of cytotoxic T cells [1].
Hematological Malignancies: In classic Hodgkin lymphoma, maraviroc inhibits the clonogenic growth of tumor cells and prevents monocyte migration induced by tumor-educated mesenchymal stem cells (MSCs) [1]. It also induces apoptosis and suppresses xenograft growth in acute lymphoblastic leukemia [1].
3. Molecular Mechanism of Action
Maraviroc functions as a slow-offset, functional allosteric antagonist of the CCR5 receptor [2]. By binding to the receptor, it prevents the internalization of CCR5 and blocks the binding of its natural ligands, such as CCL5 (RANTES), CCL3, and CCL4 [1][2]. This blockade disrupts several critical downstream signaling cascades in cancer cells and stromal cells:
Inhibition of Survival and Proliferation Pathways: Blocking CCR5 with maraviroc prevents the activation of the PI3K/Akt and NF-κB pathways, which are essential for cancer cell survival, migration, and integrin activation (e.g., αvβ3 integrin) [3]. It also inhibits the mammalian target of rapamycin (mTOR) pathway, leading to the downregulation of cyclin D1 and c-Myc, thereby halting cell cycle progression and proliferation [1].
Disruption of DNA Damage Repair: CCR5 signaling governs DNA damage repair mechanisms and promotes cancer stem cell (CSC) expansion. Maraviroc impairs homology-directed repair and single-strand annealing pathways. By doing so, it renders cancer cells significantly more susceptible to DNA-damaging agents like doxorubicin and γ-irradiation [1][3].
Metabolic Reprogramming and Angiogenesis: CCR5 engagement normally stimulates glucose uptake, glycolysis, and fatty acid synthesis via Akt phosphorylation. Maraviroc disrupts this metabolic reprogramming [1]. Furthermore, it inhibits angiogenesis by reducing endothelial cell migration and the secretion of vascular endothelial growth factor (VEGF) [1][3].
4. Structure-Activity Relationship (SAR)
Maraviroc was discovered through high-throughput screening of a massive compound library using a chemokine radioligand-binding assay, followed by an extensive medicinal chemistry optimization effort involving nearly 1,000 molecules [2]. It was specifically optimized for high potency against the CCR5 receptor, broad-spectrum antiviral activity, favorable pharmacokinetic characteristics, and high selectivity against other human cellular targets [2]. Structurally, maraviroc binds deep within the transmembrane pocket of the CCR5 G-protein-coupled receptor (GPCR). Rather than acting as a simple competitive orthosteric antagonist at the extracellular ligand-binding site, it acts as an allosteric modulator. This specific binding mode locks the receptor in an inactive conformation, which is responsible for its characteristic slow-offset kinetics and potent functional antagonism [2].
5. Current Limitations
Despite its therapeutic promise, the use of maraviroc in oncology faces several limitations:
Redundancy of the Chemokine System: The chemokine network is highly complex and redundant. Blocking a single receptor like CCR5 may lead to compensatory signaling through other chemokine receptors or alternative ligands, potentially limiting long-term efficacy [4].
Pharmacokinetics and Drug Resistance: Maraviroc is a substrate for cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (multidrug resistance protein 1, MDR1). The overexpression of MDR1 in many cancer cells can lead to the active efflux of maraviroc, reducing its intracellular concentration and contributing to drug resistance [1].
Receptor Saturation Requirements: Clinical data from HIV trials indicate that very high levels of CCR5 receptor saturation (>80%) are required for efficacy [2]. Achieving and maintaining such high saturation levels consistently within dense, poorly vascularized solid tumors may prove challenging.
Heterogeneous Target Expression: In certain cancers, such as metastatic colorectal cancer, CCR5 expression can be "patchy" or restricted to specific areas like the invasive margin. While maraviroc has shown efficacy even in tumors with patchy expression, this heterogeneity complicates patient stratification and the identification of ideal candidates for therapy [1].
6. Future Perspectives
The future of maraviroc in oncology is heavily focused on combination therapies, leveraging its ability to modulate the immune microenvironment and sensitize tumors to other treatments.
Combination with Immune Checkpoint Inhibitors (ICIs): Because maraviroc reduces immunosuppressive cells (like Tregs and M2-TAMs) and promotes an inflamed TME, it is a strong candidate for combination with ICIs. Clinical trials, such as the PICCASSO phase I trial, have evaluated maraviroc combined with pembrolizumab (an anti-PD-1 antibody) in refractory microsatellite-stable (MSS) metastatic colorectal cancer. The combination was feasible, safe, and yielded a higher-than-expected overall survival rate in a heavily pretreated population [1][3]. Another trial, LUMINESCENCE, is currently exploring maraviroc in combination with ipilimumab and nivolumab for advanced colorectal and pancreatic cancers [3][5].
Combination with Chemotherapy: Given that CCR5 signaling enhances DNA damage repair and promotes cancer stem cell survival, combining maraviroc with DNA-damaging chemotherapies (e.g., doxorubicin, carboplatin) presents a rational strategy to overcome chemoresistance and improve cytotoxic efficacy [1][3].
Overall, the repurposing of maraviroc represents a paradigm shift in targeting the tumor microenvironment, offering a novel avenue to enhance the efficacy of existing oncological regimens and improve outcomes for patients with refractory cancers.
