ALK inhibitors are potential anti cancer drugs that act on tumours with variations

by Selleckchem | Dec 19 2012

The ALK (anaplastic lymphoma kinase) gene encodes a tyrosine kinase belonging to the insulin receptor superfamily. ALK is abundantly expressed in neural tissue during embryogenesis, but levels fall during early development, so that in adults it is expressed only in rare scattered neural cells (Iwahara et al., 1997; Morris et al., 1997; Webb et al., 2009; Ardini et al., 2010). ALK was Abl activation originally identified in anaplastic large cell lymphoma (ALCL) cells as the product of a recurring chromosomal translocation, t (2;5; p23;q35), between the ALK gene on chromosome 2 and the nucleophosmin (NPM) gene on chromosome 5, which gives rise to expression of the NPM?CALK fusion protein (Morris et al., 1994).
The oncogenic potential of NPM?CALK, which contains a constitutively activated ALK kinase domain, was subsequently demonstrated in several different preclinical models, confirming ALK inhibition its role in the pathogenesis of ALCL (Shiota et al., 1994; Drexler et al., 2000). In addition to ALCL,ALK gene translocations or activating point mutations were identified in other rare tumor types, including inflammatory myofibroblastic tumors (IMT) and neuroblastoma (Webb et al., 2009; Ardini et al., 2010). IMT is a rare tumor of mesenchymal origin that affects young individuals, with approximately 50% of cases bearing a chromosomal translocation involving the ALK gene, fused to many different N-terminal partners (Griffin et al., 1999), while Src activation neuroblastoma is a rare pediatric solid tumor and originates from neural cell-derived tissue, giving tumor masses localized mainly at the level of the adrenal glands (Maris et al.
, 2007). In neuroblastoma, ALK gene amplification and point mutations are found as recurring events, rather than gene translocation. Notwithstanding the substantial evidence linking activated ALK kinase to tumorigenesis in these rare tumors, it is fair to say that the considerable current enthusiasm for ALK as target for cancer therapy is Tie 2 largely driven by the relatively recent finding of a recurring ALK gene translocation in a significant subset (ca. 5%) of non-small-cell lung cancer (NSCLC, Rikova et al., 2007; Soda et al., 2007). In ALK-positive NSCLC, ALK gene rearrangement most often involves an inversion within the short arm of chromosome 2 (between loci 2p21 and 2p23), leading to expression of echinoderm microtubule associated protein like 4 (EML4)?C ALK, an oncogenic fusion protein composed of the N-terminal portion of EML4 and the entire intracellular portion of ALK.
As with NPM?CALK, there is much convincing preclinical evidence in support of the oncogenic nature of EML4?CALK, the requirement for ALK kinase activity in maintenance of EML4?CALK-dependent tumor cell growth and of the capacity of selective small molecule kinase inhibitors of ALK to induce cell death in such tumors (Christensen et al., 2007; Galkin et al., 2007; Choi et al., 2008; Koivunen et al., 2008; McDermott et al., 2008; Soda et al., 2008). Subsequent studies of tissue samples from NSCLC patients aimed at further characterizing ALK-positiveNSCLChave led to the identification of a relatively well defined potential patient population, characterized by specific FGFR inhibition clinical?Cpathological features.
It appears that ALK-positive patients tend to be younger than the median age for lung cancer patients and are, in general, never-smokers, or former light smokers, while at the histological level, ALKpositive tumors are almost exclusively adenocarcinomas, with a clear component of the signet-ring cell type (Inamura et al., 2008; Shaw et al., 2009; Solomon et al., 2009; Kwak et al., 2010). The presence of EML4?CALK rearrangement appears to be mutually exclusive with KRAS and EGFR mutations, further supporting a role for ALK as a unique driver of malignancy in these patients, though interestingly, an exception is possibly represented by the recent description of a small fraction of crizotinib-na?ve patients reported to possess both EML4?CALK rearrangement and EGFR mutations (Sasaki et al., 2011), as will be further commented below.