by ecancer reporter Clare Sansom

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, with over three-quarters of lung carcinomas diagnosed being classified as this type. 

Although its prognosis is rather better than that for small-cell disease it is still poor, with an overall five year survival rate of less than 20%. It is itself a heterogeneous condition, divided into three main histological subtypes. 

Furthermore, recent advances in elucidating the molecular profile of tumours and in developing targeted therapies have led to an understanding of the molecular complexity of this disease. 

So-called “driver” mutations have been identified in a proportion of non-small cell lung tumours, but 40% of such tumours still lack an identifiable driver mutation.

Recently, attention has been focused on the gene ROS1, which encodes a receptor tyrosine kinase and which has been identified as being involved in chromosomal translocations in some cancers. 

Fusions between this gene, which is located on the long arm of chromosome 6, and a neighbouring one were first identified in glioblastomas but have since been observed in some NSCLC samples. 

These tumours have constitutive kinase activity and are generally sensitive to kinase inhibitors. A large, international group of researchers led by A. John Iafrate of Massachusetts General Hospital, Boston, MA, USA has now compared the outcome and clinical characteristics of non-small cell lung cancers carrying this mutation with those without.

The researchers identified a series of 1,073 patients with NSCLC who were treated at participating institutions in the USA and China. 

Demographical, pathological and clinical details including outcome were obtained for each patient. Each tumour was screened for chromosomal rearrangements in ROS1 using fluorescence in situ hybridisation (FISH) and the presence of this rearrangement was confirmed in 18 tumours (a prevalence rate of 1.68%).

Real time PCR and sequencing of ROS1 rearrangement positive tumours was used to identify the ROS1 translocation partner; the most common partner, observed in five cases, was found to be CD74. Interestingly, ROS1 rearrangements were found to be mutually exclusive from rearrangements in the gene ALK, which also encodes a kinase); ALK rearrangements were observed in 31 other tumours (prevalence 2.89%).

Analysis of the clinical characteristics of the patients whose tumours were identified as bearing ROS1 rearrangements showed some common features and suggested that this rearrangement defines a unique subtype of this cancer. 

Those patients with ROS1 rearrangement positive tumours were, on average, younger than others in the sample (mean age 49.8 years); they were all diagnosed with the histological subtype of adenocarcinoma, although with a wide distribution of tumour grade; and they were more often non-smokers. 

The overall survival of patients bearing tumours with this rearrangement did not differ significantly from that of other patients in this sample.

The kinase inhibitor crizotinib, developed primarily to inhibit ALK and MET kinases, has previously been found to inhibit the growth of a NSCLC cell line known to have a ROS1 rearrangement. 

Iafrate and his co-workers confirmed this activity by showing that the drug could inhibit ROS1 phosphorylation in cells transfected with a CD74-

ROS1 fusion gene expression construct.  They then sought to test this finding in the clinic by enrolling a NSCLC patient with a known ROS1 rearrangement in an expansion cohort of a Phase I study of crizotinib for this disease. This 31 year old male never-smoker had previously failed to respond to the EGFR inhibitor erlotinib. 

Eight weeks after starting treatment with critozinib his tumour had shrunk dramatically, and this response continued for at least six months. 

This remarkable result, admittedly in a single patient, suggests that the novel molecular subtype of NSCLC characterised by chromosomal rearrangements affecting ROS1 may also be characterised by sensitivity to critozinib and, by implication, to other small-molecule inhibitors of this kinase.

Reference

Bergethon, K., Shaw, A.T., Ignatius Ou, S.H. and 19 others (2012). ROS1 Rearrangements Define a Unique Molecular Class of Lung Cancers. J. Clin. Oncol. (2012), published ahead of print 3 January 2012. doi: 10.1200/JCO.2011.35.6345