MUC4 mucin- a therapeutic target for pancreatic ductal adenocarcinoma

ABSTRACT

Introduction: Pancreatic cancer (PC) is characterized by mucin overexpression. MUC4 is the most differentially overexpressed membrane-bound mucin that plays a functional role in disease progression and therapy resistance.

Area covered: We describe the clinicopathological significance of MUC4, summarize mechanisms contributing to its deregulated expression, review preclinical studies aimed at inhibiting MUC4, and discuss how MUC4 overexpression provides opportunities for developing targeted therapies. Finally, we discuss the challenges for developing MUC4-based therapeutics, and identify areas where efforts should be directed to effectively exploit MUC4 as a therapeutic target for PC.

Expert opinion: Studies demonstrating that abrogation of MUC4 expression reduces proliferation and metastasis of PC cells and enhances sensitivity to therapeutic agents affirm its utility as a therapeutic target. Emerging evidence also supports the suitability of MUC4 as a potential immunotherapy target. However, these studies have been limited to in vitro, ex vivo or in vivo approaches using xenograft tumors in immunodeficient murine models. For translational relevance, MUC4-targeted therapies should be evaluated in murine models with intact immune system and accurate tumor microenvironment. Additionally, future studies evaluating MUC4 as a target for immunotherapy must entail characterization of immune response in PC patients and investigate its association with immunosuppression and survival.

KEYWORDS:

• MUC4
• miRNA
• natural products
• pancreatic cancer (PC)
• therapeutic target
• vaccine

Article highlights

• MUC4 is one of the most differentially overexpressed membrane-bound mucins in pancreatic cancer and functionally contributes to tumor growth, metastasis, chemoresistance, and poor survival.

• Well-characterized mechanisms of MUC4 deregulation, its altered glycosylation, existence of multiple splice variants, and multiplicity of TR epitopes make it an attractive target for therapy of pancreatic cancer.

• Inhibition of MUC4 expression with miRNAs, siRNAs, pharmacological agents and natural products in pancreatic cancer cells reduces their proliferative and invasive properties in vitro and in vivo and restores sensitivity to chemotherapeutic agents.

• Several challenges need to be overcome to develop MUC4-based targeted therapies, and overcoming those impediments will require development of novel reagents, models and delivery platforms.

• Understanding the interplay of MUC4 with the immune system and its role in establishing an immunosuppressive tumor microenvironment, characterization of MUC4-specific immune responses in pancreatic cancer patients, and development of human MUC4-expressing transgenic models are critical for realizing the true potential of MUC4 as a target for immunotherapy.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

S. Batra receives funding from grants R01 CA183459, RO1 GM113166, SPORE P50 CA127297 and EDRN U01 CA200466 from the National Institutes of Health. M. Jain receives funding from grant R01 CA195586 from the National Institutes of Health.