[ABL1, SRC and other non-receptor protein tyrosine kinases as new targets for specific anticancer therapy]

Abstract

Non-receptor protein tyrosine kinases are responsible for signal transduction during many physiologic cellular processes, including cell growth and proliferation, apoptosis, differentiation, regulation of actin cytoskeleton, cell shape, adhesion, motility and migration. Aberrant activity of protein tyrosine kinases (acquired as a result of chromosomal translocation or point mutation) has been implicated in the stimulation of cancer growth and progression, the induction of drug-resistance, tumour neovascularization, tissue invasion, extravasation and the formation of metastases. Small molecule tyrosine kinase inhibitors interfere with these pathophysiological circuits by blocking the signalling cascades triggered by the aberrantly activated protein tyrosine kinases (e.g. BCR-ABL1, FIP1L1-PDGFRA or ETV6-PDGFRB).Tyrosine kinase inhibitors (imatinib, nilotinib, dasatinib) now belong to established anti-cancer agents with clinical activity in patients with CML, Ph+ ALL, and myeloid neoplasms with overexpression of PDGFRA, PDGFRB and wild-type KIT. New generation tyrosine kinase inhibitors (e.g. dasatinib) with extended activity against SRC and EPH kinases belong to promising anti-cancer agents with documented preclinical activity in several solid tumours (e.g. prostate cancer).