Signaling pathways as therapeutic targets in biliary tract cancer

ABSTRACT

Introduction: The incidence of biliary tract cancer (BTC) is increasing, and the disease is frequently diagnosed during advanced stages, leading to poor overall survival. Limited treatment options are currently available and novel therapeutic approaches are needed. A number of completed clinical trials have evaluated the role of chemotherapy for BTC, demonstrating a marginal benefit. Thus, there is increased interest in applying targeted therapies for this disease.

Areas covered: This review article summarizes the role of chemotherapeutic regimens for the treatment of BTC, and highlights key signal transduction pathways of interest for targeted inhibition. Of particular interest are the MEK or MAP2K (mitogen-activated protein kinase kinase), phosphatidylinositol-3 kinase (PI3K) and signal transducer and activator of transcription-3 (STAT3) pathways. We discuss the available data on several promising inhibitors of these pathways, both in the pre-clinical and clinical settings.

Expert opinion: Future treatment strategies should address targeting of MEK, PI3K and STAT3 for BTC, with a focus on combined therapeutic approaches.

KEYWORDS:

• Biliary tract cancer
• cholangiocarcinoma
• targeted therapy
• STAT3
• PI3K
• MEK

Article highlights

• Poor survival and limited treatment options for biliary tract cancer (BTC) demonstrate the need for novel therapeutic approaches.

• A summary of the various chemotherapeutic regiments of both published and ongoing clinical trials in BTC has been presented.

• Key signal transduction pathways are of interest for targeted therapy in BTC, with particular focus and rationale for targeting mitogen-activated protein kinase kinase (MEK), phosphatidylinositol-3 kinase (PI3K), and signal transducer and activator of transcription-3 (STAT3) pathways.

• Several small molecule inhibitors designed to inhibit MEK, PI3K, and STAT3 are available for potential application to BTC.

This box summarizes key points contained in the article.

Declaration of interest

G. Lesinski declares having received a research funding grant to his institution from Array Biopharma in 2014. The authors have no other 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 apart from those disclosed.

Additional information

Funding

This paper was not funded.