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  • Review Article
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Factors underlying sensitivity of cancers to small-molecule kinase inhibitors

Nature Reviews Drug Discovery volume 8, pages 709–723 (2009)Cite this article

Key Points

  • There are 518 predicted protein kinases encoded by the human genome, and many of these have been implicated in various aspects of tumorigenesis by virtue of overexpression and/or mutational activation. Consequently, kinases have emerged as a potentially important class of targets for the development of therapeutic anti-cancer agents. There has been a tremendous and rapidly expanding effort during the past decade to develop and test kinase-targeted antibodies as well as small-molecule inhibitors of catalysis.

  • Despite early scepticism about the ability to develop selective and potent kinase inhibitors, there are now 10 kinase inhibitors approved for treatment of patients with cancer on the basis of good clinical efficacy. These include the Bcr-Abl kinase inhibitor imatinib, which has become the standard of care for treatment of patients with chronic myelogenous leukaemia, and erlotinib, which is widely used in patients with chemotherapy-refractory non-small cell lung cancer.

  • The expanding clinical use of kinase inhibitors has revealed that they are typically effective in subsets of treated patients, and many factors seem to contribute to this variable clinical responsiveness. Among the most critical determinants of response to the selective kinase inhibitors is the presence of activating mutations in the gene encoding the targeted kinase — which are well correlated with drug sensitivity.

  • Several additional factors have been implicated in the variable clinical response among treated patients. These include: genomic alterations that have an impact on the signalling pathway mediated by the targeted kinase, germline polymorphic differences that have an impact on drug metabolism, distinct features of the tumour microenvironment and the emergence of acquired drug resistance. Each of these factors may present an opportunity to develop strategies to improve clinical outcomes with kinase inhibitors and to broaden their therapeutic utility.

  • Collectively, such findings have highlighted the importance of 'personalized cancer medicine', an emerging approach to cancer therapy that exploits the increasingly appreciated genomic heterogeneity among patients with cancer — even those with histologically indistinguishable disease — and aims to match patients with appropriate drugs, many of which are currently kinase inhibitors.

Abstract

Selective small-molecule kinase inhibitors have emerged over the past decade as an important class of anti-cancer agents, and have demonstrated impressive clinical efficacy in several different diseases, including relatively common malignancies such as breast and lung cancer. However, clinical benefit is typically limited to a fraction of treated patients. Genomic features of individual tumours contribute significantly to such clinical responses, and these seem to vary tremendously across patients. Additional factors, including pharmacogenomics, the tumour microenvironment and rapidly acquired drug resistance, also contribute to the clinical sensitivity of various cancers, and should be considered and applied in the development and use of new kinase inhibitors.

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Figure 1: The role of drug metabolism in the variable response to selective kinase inhibitors.
Figure 2: Mechanisms of acquired resistance to EGFR TKIs in lung cancer.

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Acknowledgements

We apologize to the authors of many important publications relevant to the topics covered in the Review that we were unable to cite due to space constraints.

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Authors and Affiliations

  1. Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA

    Pasi A. Jänne & Nathanael Gray

  2. Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts, USA

    Jeff Settleman

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Correspondence to Jeff Settleman.

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P.A.J. and J.S. receive royalties as patent holders related to EGFR mutation testing in lung cancer.

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Glossary

Personalized cancer medicine

The clinical strategy of matching a specific cohort of patients with cancer to an appropriate therapy on the basis of clinical features or biomarkers that are shared between the individuals in that cohort. The goal is to optimize the frequency of clinical responses to treatment and to avoid treating patients with agents that are unlikely to yield clinical benefit.

Small-molecule kinase inhibitors

Synthetic or natural compounds, typically of a molecular size of less than 1,000 Daltons, that selectively inhibit particular kinases, typically through ATP-competitive interactions with the catalytic pocket or through allosteric interactions with other regions of the kinase.

Protein kinases

A class of cellular enzymes that share an ATP-dependent catalytic activity that results in the covalent attachment of a phosphate group to amino acids (serines, threonines or tyrosines) in specific peptide sequences of substrate proteins. There are an estimated 518 protein kinases encoded by the human genome. This subgroup of genes constitutes the human kinome.

Off-target activity

Drug activity that results from interaction with, and consequent effects on, unintended cellular targets.

Oncogene addiction

The phenomenon wherein tumour cells, despite the accumulation of multiple genetic lesions that contribute to malignancy, retain a requirement for the maintained activity of a single activated gene or associated pathway for their sustained proliferation and/or survival.

Germline polymorphisms

Polymorphic differences at a defined genomic locus in germline-derived (constitutional) tissue across a human population.

Pharmacokinetics

The effects of the body on drug efficacy and metabolism.

Adjuvant therapy

Any therapy delivered subsequent to a primary treatment with the goal of increasing treatment efficacy.

Pharmacogenomics

Relating to the influence of genetic variation in the drug response among treated patients.

Tumour microenvironment

The tissue environment closely associated with tumor cells. This typically includes vasculature, stroma-derived cells, and infiltrating immune cells, the presence of which can substantially impact clinical course and response to treatment.

Xenografts

Cancer cells transplanted into animals, such as mice, to examine tumorigenic properties and responses to treatment in vivo.

Cell autonomous and non-cell autonomous

Properties of tumour cells that are solely attributed to the tumour cell irrespective of its environment are described as 'cell autonomous', whereas tumour cell properties that are dependent on the cellular context (for example, surrounding stromal cells or available cytokines) are described as 'non-cell autonomous'.

Biomarkers

Readily detectable cellular molecules — typically, gene mutations, proteins, or RNAs — the presence or level of which is associated with, or predictive of, a clinical outcome.

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Jänne, P., Gray, N. & Settleman, J. Factors underlying sensitivity of cancers to small-molecule kinase inhibitors. Nat Rev Drug Discov 8, 709–723 (2009). https://doi.org/10.1038/nrd2871

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