Chemoresistance and resistance to targeted therapies in biliary tract cancer: what have we learned?

ABSTRACT

Introduction

Biliary tract cancer (BTC), including intra- and extrahepatic cholangiocarcinoma and gallbladder cancer, is a rare and highly difficult to manage human malignancy. Besides late diagnosis and associated unresectability, frequently observed unresponsiveness toward and recurrence following chemotherapy or targeted therapy essentially contribute to the dismal prognosis of BTC patients.

Areas covered

The review provides an update on individual mechanisms involved resistance of BTC toward conventional chemotherapy as well as targeted therapies. We review the distinct mechanisms of pharmacoresistance (MPRs) which have been defined in BTC cells on a molecular basis and examine the specific consequences for the various approaches of chemo-, targeted or immunomodulatory therapies.

Expert opinion

Based on currently available experimental and clinical data, the present knowledge about these MPRs in BTCs are summarized. While some possible tactics for overcoming these mechanisms of resistance have been investigated, a BTC-specific and efficient approach based on comprehensive in vitro and in vivo experimental systems is not yet available. Additionally, a reliable monitoring of therapy-relevant cellular changes needs to be established which allows for choosing the optimal drug (combination) before and/or during pharmacological therapy.

KEYWORDS:

• Biliary tract cancer
• chemosensitization
• chemotherapy
• mechanisms of chemoresistance
• targeted therapy

Article highlights

• Several specific mechanisms of chemoresistance (MOCs) or – more general – pharmacoresistance (MPRs) have been identified and systematically defined for biliary tract cancer (BTC).

• This conceptual framework will prove valuable to systematically investigate approaches to increase the efficacy of chemo- and targeted therapy in BTC.

• Different approaches have been investigated to overcome resistance in BTC ranging from ‘simple’ chemosensitizers, chemical drug modification to more specific genetic therapy.

• Current challenges include the general transferability to clinical practice calling for more comprehensive tumor models that take into account complex tumor tissue properties possibly influencing (chemo-)resistance.

• For efficient clinical application, identification of ‘real-time’ molecular biomarkers with prognostic significance for chemoresistance (prior and during therapy) is central.

Conflict of interest

M.D.P. received honoraria for talks and/or for advisory function from Amgen, Merck KGaA, Lilly, Sanofi, Roche, Taiho, Servier, MSD, BMS, Incyte, Onkowissen, G1.

N.D. received honoraria for advisory function of Boehringer Ingelheim Pharma GmbH & Co.

O.M. is an employee of Boehringer Ingelheim Pharma GmbH & Co, Germany. Boehringer Ingelheim had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

S.S. received honoraria for talks and/or for advisory function from Amgen, Bayer, Merck KGaA, Lilly, Sanofi, Roche, Takeda, Taiho, SIRTEX and Samsung.

The other authors declare no conflict of interest related to this publication. 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.