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

The BCR-ABL fusion protein and Src family tyrosine kinases (SFKs) represent a critical dual-target axis in oncology, particularly in hematologic malignancies [1]. BCR-ABL is a constitutively active non-receptor tyrosine kinase resulting from the reciprocal translocation between chromosomes 9 and 22, known as the Philadelphia chromosome, which is the hallmark of chronic myeloid leukemia (CML) [2]. Src family kinases, including members like Src, Lyn, and Hck, are non-receptor tyrosine kinases that regulate diverse cellular processes such as adhesion, migration, and survival [3]. In many cancers, SFKs are overexpressed or hyperactivated, often cooperating with BCR-ABL to drive disease progression and mediate resistance to first-generation kinase inhibitors like imatinib [4]. Therapeutic agents targeting both BCR-ABL and SFKs, such as dasatinib and bosutinib, are designed to overcome this resistance and provide more potent inhibition of leukemic cell growth [5]. By blocking the ATP-binding site of these kinases, these drugs disrupt downstream signaling cascades like PI3K/Akt and STAT5, leading to cell cycle arrest and apoptosis in malignant cells [6]. This dual inhibition is particularly effective in treating patients who have developed resistance to imatinib through SFK-mediated pathways or specific BCR-ABL mutations [4, 5]. Beyond leukemia, SFKs are also implicated in the progression of various solid tumors, making them a broad interest in oncology research [3].

Other names

BCR-ABL1Philadelphia chromosome kinaseSFKsc-SrcLynHckFynYesFgrLckBlk

These drugs act as ATP-competitive inhibitors that bind to the kinase domain of both the BCR-ABL fusion protein and various members of the Src family of tyrosine kinases, preventing the phosphorylation of downstream substrates and inhibiting oncogenic signaling pathways [5, 6].