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  • Review Article
  • Published:

Cancer drug resistance: an evolving paradigm

Key Points

  • Tumour resistance to chemotherapy and molecularly targeted therapies limits the effectiveness of current cancer therapies.

  • Toxicity to normal tissues limits the amount of drug that can be systemically administered, and pharmacokinetic effects (absorption, distribution, metabolism and elimination (ADME)) limit the amount of drug that reaches the tumour.

  • At the level of the tumour, various resistance mechanisms can operate, such as increased drug efflux, mutations of the drug target, DNA damage repair, activation of alternative signalling pathways and evasion of cell death.

  • Tumour resistance can be intrinsic (that is, present before treatment), or acquired during treatment by various therapy-induced adaptive responses.

  • Tumours are heterogeneous; therefore, resistance can also arise by positive selection of a drug-resistant tumour subpopulation.

  • High-throughput screening techniques and systems biology approaches have the power to identify novel mechanisms of drug resistance and molecular signatures and genotypes that predict tumour response.

  • Increasingly, predictive biomarkers will be used clinically to stratify patients to receive specific therapeutics.

  • Improved understanding of the molecular basis of resistance will inevitably lead to the clinical assessment of rational drug combinations in selected patient populations.

Abstract

Resistance to chemotherapy and molecularly targeted therapies is a major problem facing current cancer research. The mechanisms of resistance to 'classical' cytotoxic chemotherapeutics and to therapies that are designed to be selective for specific molecular targets share many features, such as alterations in the drug target, activation of prosurvival pathways and ineffective induction of cell death. With the increasing arsenal of anticancer agents, improving preclinical models and the advent of powerful high-throughput screening techniques, there are now unprecedented opportunities to understand and overcome drug resistance through the clinical assessment of rational therapeutic drug combinations and the use of predictive biomarkers to enable patient stratification.

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Figure 1: General principles of drug resistance.
Figure 2: Summary of downstream factors that influence drug resistance.
Figure 3: Apoptosis signalling and therapeutic targeting.
Figure 4: Mechanisms of resistance to molecularly targeted therapies as exemplified by EGFR, RAF and MEK inhibitors.

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Acknowledgements

This work was supported by a grant from Cancer Research UK, C212/A13721.

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Correspondence to Daniel B. Longley.

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Competing interests

P.G.J. is employed by Almac Diagnostics and has an ownership interest in both Almac Diagnostics and Fusion Antibodies. He is a consultant/advisor for, and has received honoraria from, Chugai Pharmaceuticals, Sanofi-Aventis and Pfizer. The other authors declare no competing financial interests.

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Glossary

Antimetabolites

A class of drug that interferes with normal cellular metabolism by disrupting the function of a normal cellular metabolite. Examples that are used as anticancer therapies include 5-fluorouracil, methotrexate and pemetrexed.

Gatekeeper residue

A conserved residue that lies at the opening of the ATP-binding pocket in many kinases. Mutations in these sites are frequently observed as a resistance mechanism to inhibitors of oncogenic kinases.

Mismatch repair

(MMR). A mechanism that corrects base–base mismatches, or insertion and deletion mismatches that are caused by DNA polymerase errors during DNA replication.

Nucleotide-excision repair

(NER). A mechanism of repair for DNA damage caused by crosslinking of DNA bases. It is particularly important for resistance to platinum-based chemotherapeutics.

BH3 profiling

A functional assay that can be used to measure how close a cell is to committing to apoptosis. It involves measuring the mitochondrial response to peptides derived from the BH3 domain of BCL-2 family members.

Mitochondrial priming

A measurable property that determines the proximity of a cell to the apoptotic threshold based on its BH3 profile.

Prodiginines

Bioactive secondary metabolites that are produced by bacteria and that have immunosuppressant, anticancer and antimalarial activities.

Fragment-based design

An NMR-based approach that identifies small organic molecules that bind to adjacent sites in a target molecule with relatively low affinity. Linking of two molecules that bind to adjacent sites then generates high-affinity ligands or inhibitors.

Mediator transcription complex

A large (1.2 MDa) multiprotein complex of up to 30 subunits that regulates transcription from a diverse set of RNA polymerase II-controlled promoters.

Orthogonal therapies

Two therapies are considered orthogonal if they target a cancer in two different ways such that a resistance mechanism for the first therapy is unlikely to suppress the activity of the second therapy and vice versa.

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Holohan, C., Van Schaeybroeck, S., Longley, D. et al. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 13, 714–726 (2013). https://doi.org/10.1038/nrc3599

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