Abstract
In 2007, the ALK tyrosine kinase was described as a potential therapeutic target for a subset of non-small-cell lung cancer patients. Clinical proof of concept, culminating in the recent approval by the Food and Drug Administration of the Pfizer drug crizotinib followed in record time. The drug was approved together with a companion diagnostic for detection of patients eligible for therapy. This remarkable example of the coming of age of personalized medicine in cancer therapy is hopefully only an auspice of things to come in a rapidly developing field. Perhaps unsurprisingly, however, the appearance of clinical acquired resistance to crizotinib was observed early on in clinical testing, with the identification of several ALK secondary point mutations which diminish drug efficacy and which open the way for development of second-generation inhibitors. It is also emerging that acquired resistance to crizotinib may additionally occur through ALK-independent mechanisms, which still need to be elucidated in detail. Here we discuss the factors that led to such a rapid approval of a targeted agent, and we describe the second-generation compounds currently in development.
Highlights
The ALK gene encodes a tyrosine kinase belonging to the insulin receptor superfamily
The appearance of clinical acquired resistance to crizotinib was observed early on in clinical testing, with the identification of several ALK secondary point mutations which diminish drug efficacy and which open the way for development of second-generation inhibitors
ALK was 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–ALK fusion protein (Morris et al, 1994)
Summary
The ALK (anaplastic lymphoma kinase) gene encodes a tyrosine kinase belonging to the insulin receptor superfamily. Subsequent studies of tissue samples from NSCLC patients aimed at further characterizing ALK-positive NSCLC have led to the identification of a relatively well defined potential patient population, characterized by specific clinical–pathological 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–ALK 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-naïve patients reported to possess both EML4–ALK rearrangement and EGFR mutations (Sasaki et al, 2011), as will be further commented below
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