Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL) and Src family kinases (SFK) (BCR-ABL/SFK)

The BCR-ABL fusion protein is a constitutively active tyrosine kinase produced by the Philadelphia chromosome translocation, t(9;22)(q34;q11), which is the defining molecular driver of chronic myeloid leukemia (CML) and a significant proportion of acute lymphoblastic leukemia (ALL) [3, 12]. This chimeric protein activates a network of signaling pathways, including PI3K/Akt and Ras/MAPK, to promote uncontrolled cell growth and inhibit programmed cell death [4, 18]. Src family kinases (SFKs), such as Lyn, Hck, and Fgr, are non-receptor tyrosine kinases that are frequently overexpressed or hyperactivated in BCR-ABL-positive cells, contributing to disease progression and mediating resistance to early-generation tyrosine kinase inhibitors (TKIs) [5, 7, 10]. Dual BCR-ABL and Src family kinase inhibitors, such as dasatinib and bosutinib, were developed to provide broader and more potent kinase inhibition, effectively targeting both the primary oncogenic driver and the compensatory SFK signaling [2, 6, 14]. These drugs act by competitively binding to the ATP-binding site within the kinase domains, thereby blocking the phosphorylation of substrate proteins and inducing apoptosis in malignant cells [6, 12, 19]. Therapeutic management involves regular monitoring of BCR-ABL1 transcript levels and vigilance for specific adverse effects, including pleural effusion, myelosuppression, and cardiovascular complications [9, 11, 13].

Other names

Philadelphia chromosome fusion protein and SFKBcr-Abl1 and Src kinasesp210 BCR-ABL and Src family kinasesp190 BCR-ABL and Src family kinases

ATP-competitive inhibition of the tyrosine kinase domains of both the BCR-ABL fusion protein and Src family kinases, preventing the phosphorylation of downstream substrates and inhibiting oncogenic signaling pathways.