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Role of ABL family kinases in cancer: from leukaemia to solid tumours

Key Points

  • ABL1 was first discovered more than 30 years ago as the oncogene in the Abelson murine leukaemia virus and was later identified as an oncogene that is associated with chromosome translocations in human leukaemias. Recently, activation of ABL1 and ABL2 has been detected in solid tumours.

  • Activation of ABL kinases in solid tumours is driven by enhanced expression (amplification or increased mRNA levels) and/or by increased enzymatic activity downstream of hyperactive receptor tyrosine kinases, SRC, chemokine receptors, oxidative stress, assembly of activating protein complexes and inactivation of negative regulatory proteins.

  • Disruption of cell polarity occurs early during tumorigenesis. Activation of ABL kinases results in dramatic inversion of epithelial apical–basal polarity by disrupting β1 integrin signalling and laminin assembly. Thus, activated ABL kinases may regulate early steps of tumour initiation.

  • ABL kinases regulate the function of invadopodia, actin-rich structures that remodel the extracellular matrix during cancer cell invasion. ABL kinases are required for cancer cell invasion by regulating invadopodia components and the expression of genes that promote invasion and metastasis.

  • ABL1 and ABL2 regulate overlapping and distinct cellular processes in various cell types and may differentially contribute to tumour progression. Future studies are required to evaluate unique roles for ABL kinases not only in selected solid tumours but also in cells in the tumour microenvironment.

  • Treatment of BCR–ABL1-positive leukaemias with imatinib has emerged as the best example of the successful use of tyrosine kinase inhibitor (TKI)-targeted therapy. However, use of imatinib and related drugs is inadequate for the treatment of unselected solid tumours. The identification of new allosteric inhibitors with greater specificity against ABL kinases will allow for the evaluation of the contribution of ABL kinases for the treatment of solid tumours with hyperactive ABL kinases.

  • ABL kinases are activated during acquired resistance to chemotherapy, and ABL1 inhibition can sensitize cancer cells to cytotoxic chemotherapies and targeted TKI therapies.

Abstract

The Abelson (ABL) family of nonreceptor tyrosine kinases, ABL1 and ABL2, transduces diverse extracellular signals to protein networks that control proliferation, survival, migration and invasion. ABL1 was first identified as an oncogene required for the development of leukaemias initiated by retroviruses or chromosome translocations. The demonstration that small-molecule ABL kinase inhibitors could effectively treat chronic myeloid leukaemia opened the door to the era of targeted cancer therapies. Recent reports have uncovered roles for ABL kinases in solid tumours. Enhanced ABL expression and activation in some solid tumours, together with altered cell polarity, invasion or growth induced by activated ABL kinases, suggest that drugs targeting these kinases may be useful for treating selected solid tumours.

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Figure 1: Modular domain structure of ABL family kinases.
Figure 2: ABL activation by chromosome translocations in leukaemia.
Figure 3: Active ABL kinases regulate epithelial cell polarity through β1 integrin.
Figure 4: ABL kinases regulate cancer cell invasion.

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Acknowledgements

The authors regret that owing to space limitations they could not directly cite the work of many investigators. They thank R. Li for confocal images. The Pendergast laboratory is supported by grants from the US National Cancer Institute (NCI), including NCI grants R01CA155160 and R01CA070940 to A.M.P. The authors also acknowledge the support by training grants from the US Department of Defense Breast Cancer Research Program Fellowship W81XWH-10-1-0345 and the Pharmaceutical Research and Manufacturers of America to E.K.G., and ACS Spin-Odyssey Postdoctoral grant 11984-7-PF-10-228-01-CSM to P.S.S.P.

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Glossary

Oxidative stress

An excess of reactive oxygen species (ROS), which is caused by an imbalance between the rate of reduction and the rate of oxidation of oxygen, leading to free radical generation and damage to cellular components such as DNA and lipids.

SH3 domain

SRC homology 3 domain is a protein module that binds to proline-rich sequences.

SH2 domain

SRC homology 2 domain is a protein module that binds to tyrosine phosphorylated sites in a sequence-specific context.

SH1 domain

SRC homology 1 domain refers to the tyrosine kinase domain, which was first identified in the SRC kinase.

Focal adhesions

Sites where integrins and proteoglycan-mediated adhesions connect to the actin cytoskeleton.

Adherens junctions

Intercellular adhesion structures that tightly seal the lateral spaces between cells in simple epithelia. They contain the intercellular adhesion molecule E-cadherin, as well as β-catenin and α-catenin.

Invadopodia

Actin-rich, protrusive structures in cancer cells that promote remodelling of the extracellular matrix during tumour invasion.

Phagocytic cups

Actin-rich membrane invagination that closes to form phagosomes during phagocytosis.

Activation loop

Conserved regulatory motif that extends into the active kinase domain and that is phosphorylated in the active conformation of the kinase; the activation loop serves as a binding platform for the peptide substrate to be phosphorylated.

ERBB receptors

Family of structurally related receptor tyrosine kinases of which there are four members, EGFR (also known as ERBB1), ERBB2 (also known as HER2), ERBB3 and ERBB4.

3D cultures

A system of growing cells in a three-dimensional environment, matrix or scaffold to more closely model physiological conditions.

Apical–basal polarity

Epithelial cells are polarized, with an apical membrane that faces the external environment or a lumen and is opposite the basolateral membrane, which functions in cell–cell interactions and contacts the basement membrane.

Planar cell polarity

The coordinated polarization of cells in the plane of the tissue.

ARP2/3 complex

A seven-subunit protein complex involved in regulation of the actin cytoskeleton; mediates the nucleation of branched actin filaments.

WAVE protein complex

Mediates the activation of the Arp2/3 complex at the leading edge of migrating cells.

Monobody

Genetically engineered protein that recognizes specific antigens. Monobodies are antibody mimics.

Aromatase inhibitors

Drugs that block aromatase, the enzyme that converts androgens to oestrogens; used to treat oestrogen receptor+ patients with breast cancer by decreasing circulating levels of oestrogenic compounds.

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Greuber, E., Smith-Pearson, P., Wang, J. et al. Role of ABL family kinases in cancer: from leukaemia to solid tumours. Nat Rev Cancer 13, 559–571 (2013). https://doi.org/10.1038/nrc3563

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