Why technical aspects rather than biology explain cellular heterogeneity in ALK-positive non-small cell lung cancer

The discovery of anaplastic lymphoma kinase (ALK) gene rearrangements in a small subset of lung adenoracimonas in 2007 led to the definition of a new molecular subgroup of non small cell lung cancers (NSCLC) (1). These ALK-rearranged tumors are most commonly adenocarcinomas, often with signet ring mucinous cells, without mutation of EGFR or KRAS, and preferentially arise in non- or light smokers, but some ALK-rearranged NSCLC cases do not fit this description. A number of fusion variants have been identified; the most common being EML4-ALK fusions which are formed from inversions within the small arm of chromosome 2. The encoded proteins comprise the N-terminal portion of EML4 and the intracellular catalytic domain of ALK. A dimerization or oligomerization of these chimeric proteins leads to a constitutive activation of the ALK kinase domain (2). Other described fusion partners of ALK in lung tumors comprise KIF5B, TFG and KLC1 (3-5).