Tackling drug resistance: emerging themes in biology, technology and collaboration

Intrinsic and acquired drug resistance severely limits the efficacy and response duration of anticancer therapies. Contributing to drug resistance are the existence of self-renewing stem cell populations, heterogeneity of tumour genomes and the ability of cancer cells to engage compensatory or redundancy mechanisms. The downloads included in this Drug Discovery Today Editor’s Choice newsletter outline progress in our understanding of stem cell biology, emerging technologies for high content imaging and molecular pathway profiling of tumours, and the importance of collaboration between industrial and academic translational researchers

In the paper ‘Targeting cancer-initiating cell drug-resistance: a roadmap to a new-generation of cancer therapies?’, Alama and co-workers address perhaps the most fundamentally important challenge facing cancer researchers, physicians and patients alike. The often rapid emergence of drug resistance imparts a critical limitation to the utility of both traditional chemotherapy and the rapidly growing armamentarium of new molecularly targeted drugs. The authors describe the central role of cancer stem cells (CSCs) in this phenomenon and the range of mechanisms deployed by these cells to maintain viability. CSCs have been identified in a range of tumour types. These cells are also referred to as cancer initiating cells (CICs) as although often quiescent, they retain the ability to replicate and establish new tumours. Quiescent CICs are poorly responsive to anticancer drugs targeting hyper-proliferating cells and their elimination will necessitate the deployment of different therapeutic strategies. The authors provide an overview of drugs currently in clinical trials that target CICs and emphasise the potential for targeting CICs using immunotherapeutic strategies.

Continuing with the theme of CSCs, Michele Markestein in her paper on modelling colorectal cancer discusses recent advances in culturing colorectal stems cells using mammalian organoids, zebrafish and Drosophila as model systems for drug discovery. Progress in the colorectal CSC area has been assisted by the identification of two distinct classes of CSCs (Lgr-5 expressing and Bmi1-expressing). A major hurdle to identifying anti-CSC drugs has been developing methods to culture stem cells as their viability is dependent on interactions with the microenvironment. The paper provides an overview of progress in growing in vitro organoids from a variety of murine and human intestinal sources. In vivo systems have the advantage of retaining the complete physiology of the stem cell niche and Markstein describes how zebrafish and Drosophila provide for excellent models of the mammalian intestine amenable to genetic dissection. The author suggests that a major potential use for these systems could be unbiased high-throughput screening for drugs impacting CSC maintenance and/or differentiation.

Carragher et al. in their paper ‘Combining imaging and pathway profiling: an alternative approach to cancer drug discovery’ also focus on the problem of drug resistance. The authors discuss how two emerging and complementary technologies, phenotypic imaging and post-translational pathway profiling, when combined with relevant disease models, can inform drug discovery and drug combination studies to potentially reduce clinical attrition and counteract intrinsic and adaptive drug resistance. Advanced in vitro and in vivo imaging methodologies are now available that allow direct visualisation of cancer-associated behaviour in disease-relevant, complex biological systems. In addition, recent advances in functional proteomics have provided new insights into the dynamics of pathway activation in cancer where reverse phase protein array platforms provide a cost-effective approach to high-throughput pathway analysis. The authors argue that capturing detailed mechanistic and efficacy information in systems recapitulating the heterogeneity and complexity of malignant disease will enable more evidence-based and rational decisions to be made around progressing only those drug candidates showing significant activity in biological systems ‘closer’ to cancer. The authors also comment that optimal value will only be generated if there is productive collaboration across pharmaceutical companies and translational cancer medicine centres working together to maximise the potential of drug candidates.

Finally, on the theme of collaborations, my colleagues and I describe how Cancer Research UK (CRUK), a research-based charity, and Cancer Research Technology (CRT) the charity’s technology transfer arm; work with industry in the discovery and development of new anticancer drugs. We outline the drivers behind industry–academia collaborations and provide an overview of CRUK/CRT’s business models. These include themed alliances in the target to lead space, exemplified by the charity’s multi-project deal with AstraZeneca that aims to discover drugs targeting cancer cell metabolism, and the clinical development partnerships (CDP) initiative in drug development. Under the latter framework, CRUK’s Drug Development Office team undertake preclinical and early clinical development of agents de-prioritised by Pharma or drugs from smaller biotechnology companies lacking the resources and/or expertise to advance all of their programmes. As alluded to earlier, the ability of cancer cells to exploit compensatory pathways limits the effectiveness of anticancer drugs and points to a future where effective management of the disease will require the use of multiple drug combinations. CRUK, in partnership with the UK Experimental Cancer Medicines Network, is also working with industry to facilitate the delivery of investigator-led early phase combination trials with development stage drugs from partner pipelines. 

The reviews summarised here and available to download focus essentially on the overarching theme of drug resistance and provide the reader with valuable insight into emerging themes in biology, technology and collaboration.  


Dr Robert Williams is Chief Drug Development Scientist at Cancer Research UK’s Drug Development Office. A pharmacologist by training, Dr Williams has worked in drug discovery and development for over 25 years holding pharmaceutical industry positions in a number of therapeutic areas with Glaxo and Rhone-Poulenc Rorer, and spent 4 years in the biotechnology sector before joining Cancer Research UK in 2004. At Cancer Research UK he has overseen the progression of multiple new drug candidates into early phase cancer trials. Dr Williams served as Chairman of the Society for Medicines Research from 2008 to 2009 and is a regularly invited speaker at International Drug Discovery and Development conferences.

Share this article

More services


This article is featured in:
The View From Here


Comment on this article

You must be registered and logged in to leave a comment about this article.