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  • Review Article
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Oncogenic tyrosine kinases and the dna-damage response

Nature Reviews Cancer volume 2, pages 351–360 (2002)Cite this article

Key Points

  • Mutation and overexpression of tyrosine kinases causes their constitutive activation, often leading to malignant transformation. These oncogenic tyrosine kinases (OTKs) can induce uncontrolled growth, protection from apoptosis, inhibition of differentiation and/or dysregulation of adhesion.

  • Chemotherapy and radiotherapy have been successfully used for several decades to treat cancer, but cures are still rare events in OTK-positive tumours, because OTKs can induce resistance to cytostatic drugs and irradiation by means of at least three mechanisms:

  • Following DNA damage, OTKs enhance repair of DNA lesions (especially by homologous recombination repair).

  • They also prolong activation of cell-cycle checkpoints, providing more time for repair of otherwise lethal lesions.

  • By upregulating anti-apoptotic members of the B-cell lymphoma (BCL2) family, such as BCL-XL, OTKs provide a cytoplasmic 'umbrella', protecting mitochondria in a tumour cell from the 'rain' of apoptotic signals coming from the damaged DNA in the nucleus, thereby preventing release of cytochrome c and activation of caspases.

  • The unrepaired and aberrantly repaired DNA lesions that result from spontaneous and/or drug-induced damage can therefore accumulate in OTK-containing tumour cells, leading to genomic instability and malignant progression.

  • OTKs represent a good target for antitumour treatments. However, simultaneous treatment with OTK inhibitors and chemo- or radiotherapy might represent a more rational strategy, because OTK inhibitors should abrogate OTK-induced resistance to DNA damage and increase the efficiency of chemo-/radiotherapy. Such experimental strategies are in clinical trials.

Abstract

Oncogenic tyrosine kinases (OTKs) are involved in the induction of many types of tumour, including haematological malignancies and cancers of the breast, prostate, colon and lung. Neoplastic cells that express OTKs are usually resistant to apoptosis that is induced by DNA-damaging agents, such as cytostatic drugs and irradiation, and they display genomic instability. So, what are the mechanisms involved, and what is the potential for overcoming OTK-mediated resistance in the clinic?

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Figure 1: Genetic mechanisms in human tumours that lead to uncontrolled activation of oncogenic tyrosine kinases.
Figure 2: A model of oncogenic-tyrosine-kinase-induced drug resistance.
Figure 3: Interplay of the RAD51 paralogues during homologous recombination repair of double-strand breaks.

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Acknowledgements

This work was supported by the grants from National Institutes of Health/National Cancer Institute and American Cancer Society. T.S. is a Scholar of the Leukemia and Lymphoma Society. I would like to thank Michal O. Nowicki, whose help was essential during preparation of the figures.

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  1. Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, 19122, Pennsylvania, USA

    Tomasz Skorski

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DATABASES

Cancer.gov

chronic myelogenous leukaemia

lung cancer

prostate cancer

vulval cancer

LocusLink

ABL

AKT

ALK

ATM

BAD

BAX

BCL2

BCL-XL

BCR

BRCA1

caspase-3

CDC2

CDK2

cyclin A

cytochrome c

ERBB1

ERBB2

IGF1R

JAK2

KIT

MDM2

MLH1

MSH2

NPM

p53

p73

PDGFRβ

RAD51

RAD52

RB

SRC

STAT5

TEL

TFIIH

Medscape DrugInfo

cisplatin

daunorubicin

etoposide

Gleevec

Herceptin

mitomycin C

<i>Saccharomyces</i> Genome Database

rad51

rad52

Glossary

COMET ASSAY

Gross DNA damage can be assessed electrophoretically: intact DNA forms a 'comet head', whereas damaged DNA localizes in the tail.

RAD51 PARALOGUES

The RAD51-like proteins RAD51B, RAD51C, RAD51D, XRCC2, XRCC32 and DMC1 share significant sequence homology with RAD51 and are likely to have arisen through gene duplication and divergent evolution; the paralogues collaborate with RAD51 in homologous recombination.

TOPOISOMERASE II

An enzyme that catalyses changes in DNA topology between relaxed and supercoiled states by transiently cleaving and re-ligating both strands of the double helix.

HOMEOLOGOUS

In contrast to homologous recombination, homeologous recombination allows pairing of the invading strand with divergent sequences, resulting in unfaithful repair.

GENE CONVERSION

Non-reciprocal transfer of genetic information from one DNA duplex to the other.

SOMATIC HYPERMUTATION

Point mutations that occur in the immunoglobulin gene variable regions (and some other genes) during B-cell differentiation.

TRIPLET REPEATS

Trinucleotide repeats, the expansion of which is associated with hereditary neurological disorders.

TANDEM REPEAT LOCI

Duplicate sequences that are present in a fragment of DNA.

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Skorski, T. Oncogenic tyrosine kinases and the dna-damage response. Nat Rev Cancer 2, 351–360 (2002). https://doi.org/10.1038/nrc799

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