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Page 2 of 9 Malapelle et al. J Transl Genet Genom 2019;3:3. I https://doi.org/10.20517/jtgg.2018.29

Non-small-cell-lung cancer epidemiology
(85% of all lung cancers)

Large cell
carcinoma
2%-5%

Not otherwise
specified
20%
Adeno
carcinoma
40%
Squamous cell
carcinoma
20%-30%

Figure 1. Non-small-cell-lung cancer epidemiology

With reference to this particular cancer subtype, while treatment with ALK-tyrosine kinase inhibitor (TKI)
gives raise to no concerns and is currently considered the standard-of-care by international guidelines,
acquired resistance mechanisms to these agents represent a major clinical challenge. In fact, not only we
do not fully understand the mechanism behind this phenomenon, but we are also struggling to develop
effective drugs against the known resistance pathways.

Therefore, this paper aims to provide an up-to-date state-of-the-art review about ALK + NSCLC, genomics,
epidemiology, diagnosis, treatment and acquired resistance mechanisms, jointly with an analysis about
future developments and directions in this field.

NSCLC EPIDEMIOLOGY
Currently, lung cancer is both the most diagnosed and the deadliest cancer worldwide, and NSCLC accounts
for 85% of all cases. However, NSCLC is not one single entity, in fact, it is subdivided into adenocarcinoma
also known as lung adenocarcinoma (AC and LUAD respectively, 40% of all NSCLCs), lung squamous cell
carcinoma (or LUSC, 20%-30% of all NSCLCs ), large cell carcinoma (2%-5% of all NSCLCs) or not otherwise
specified (20% of all NSCLCs), according to the histological type [Figure 1]; and in wild-type (without any
known mutation) or mutated (“oncogene addicted”), if a mutation is present.

Presently, we are only able to specifically target oncogenic mutations in the adenocarcinoma histological
type, most notably epidermal growth factor receptor (EGFR, 15%-20% of all AC NSCLC) and ALK (4%-6% of
all AC NSCLC, mainly younger and non smokers/light smokers patients) .
[1-6]

THE ALK GENE
The ALK gene, located on the short arm of chromosome 2 (2p23), encodes for the homonymous receptor
tyrosine kinase (ALK-RTK), consisting of an extracellular, a transmembrane and a catalytic cytoplasmic
portion (that harbors the ATP binding cleft, responsible for starting phosphorylation and thus signal
[7]
transduction) .