Anaplastic lymphoma receptor tyrosine kinase (ALK) fusion protein (ALK fusion)

Anaplastic lymphoma receptor tyrosine kinase (ALK) fusion proteins are oncogenic drivers resulting from chromosomal rearrangements, most notably the EML4-ALK fusion found in non-small cell lung cancer (NSCLC) (Source: UniProt P29376; PubMed: 17625570). These fusions lead to the constitutive activation of the ALK kinase domain, which triggers downstream signaling pathways such as PI3K/AKT, MAPK/ERK, and JAK/STAT3 to promote uncontrolled cell growth and survival (Source: PubMed: 24903032). While several generations of tyrosine kinase inhibitors (TKIs) have been developed, clinical efficacy is often limited by the emergence of resistance mutations, such as the G1202R solvent front mutation (Source: PubMed: 31064780). The strategy of targeting ALK fusion proteins via E3 ligase recruitment utilizes Proteolysis Targeting Chimeras (PROTACs) to induce the ubiquitination and subsequent proteasomal degradation of the entire protein (Source: PubMed: 29300451). This approach offers a potential advantage over traditional inhibition by depleting both the catalytic and scaffolding functions of the ALK fusion protein, potentially overcoming resistance mechanisms seen with standard TKIs (Source: PubMed: 32103640).

Other names

EML4-ALKNPM-ALKALK rearrangementAnaplastic lymphoma kinase fusionALK-PROTAC targetCD74-ALKKIF5B-ALK

Targeted protein degradation (TPD) via the recruitment of an E3 ubiquitin ligase (e.g., Cereblon or Von Hippel-Lindau) to the ALK fusion protein, leading to polyubiquitination and subsequent degradation by the 26S proteasome (Source: PubMed: 29300451, 32103640).