Echinoderm microtubule-associated protein-like 4 - Anaplastic lymphoma kinase fusion protein (EML4-ALK)

The Echinoderm microtubule-associated protein-like 4 - Anaplastic lymphoma kinase (EML4-ALK) fusion protein is a chimeric oncoprotein resulting from a paracentric inversion within the short arm of chromosome 2 [Soda et al., 2007, Nature]. This genetic rearrangement fuses the N-terminal portion of the EML4 gene with the intracellular signaling domain of the ALK tyrosine kinase gene [Sabir et al., 2017, Journal of Thoracic Oncology]. The EML4 portion contains a coiled-coil domain that mediates constitutive dimerization, leading to the permanent activation of the ALK kinase domain without the need for a ligand [Lin et al., 2017, Cancer Discovery]. This aberrant signaling drives malignant transformation by activating pro-survival and proliferative pathways, most notably in approximately 3-7% of patients with non-small cell lung cancer (NSCLC) [Golding et al., 2018, Therapeutic Advances in Medical Oncology]. While highly responsive to targeted tyrosine kinase inhibitors (TKIs), the protein frequently develops secondary mutations that confer drug resistance, necessitating the development of successive generations of inhibitors [Gainor et al., 2016, Cancer Discovery].

Other names

EML4-ALK fusionEML4-ALK translocationALK fusion proteinEML4/ALKAnaplastic lymphoma kinase fusion

Small-molecule inhibition of the ALK tyrosine kinase domain by competitive binding to the ATP-binding pocket, thereby blocking downstream oncogenic signaling pathways such as RAS/MAPK, PI3K/AKT, and JAK/STAT.