Signaling by ALK in cancer

In addition to NPM, fusions of ALK with nearly 30 other 5' partners have since been identified, although these tend to occur at lower frequencies in the cancers in which they appear (reviewed in Chiarle et al, 2008; Della Corte et al, 2018; Roskoski, 2013; Hallberg and Palmer, 2016). In general, ALK fusions combine the 5' end of the partner gene which contributes a dimerization domain with the intracellular portion of the ALK receptor including the kinase domain, and lead to constitutive signaling by virtue of the partner-domain mediated dimerization (reviewed in Roskoski, 2013; Della Corte et al, 2018).

In addition to translocation events that lead to fusion proteins, the ALK gene also contributes to oncogenesis as a result of gene amplification and overexpression events, as well as being subject to activating missense mutations (reviewed in Della Corte et al, 2018; Hallberg and Palmer, 2016).

Oncogenic ALK activity can be targeted with tyrosine kinase inhibitors, although resistance often arises due to secondary mutations or activation of bypass pathways (reviewed in Roskoski, 2013; Della Corte et al, 2018; Hallberg and Palmer, 2016; Werner et al, 2017; Lovly and Pao, 2012).