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

Abstract

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.