The EML4-ALK fusion transcript was detected in 6.7% (5 out of 75) of NSCLC patients examined; these individuals were distinct from those harbouring mutations in the epidermal growth factor receptor gene.
In the present review I summarize how detection of EML4-ALK cDNA may become a sensitive diagnostic means for NSCLC cases that are positive for the fusion gene, and discuss whether suppression of ALK enzymatic activity could be an effective treatment strategy against this intractable disorder.
EML4-ALK was detected more frequently in NSCLC patients who were never or light (<10 pack-years) cigarette smokers compared with current/former smokers (6% versus 1%; P = 0.049).
The novel isoforms of EML4-ALK manifested marked oncogenic activity, and they yielded a pattern of cytoplasmic staining with fine granular foci in immunohistochemical analysis of NSCLC specimens.
These data together reinforce the pivotal role of EML4-ALK in the pathogenesis of NSCLC in humans, and they provide experimental support for the treatment of this intractable cancer with ALK inhibitors.
Furthermore, we confirmed the NKX2-1 high-level amplification in a significant subset of NSCLC and found this amplification to be mutually exclusive to ALK and EML4 rearrangements.
These results indicate that EML4-ALK rearrangements are not specific of NSCLC and raise yet unsolved questions about their role in promoting human neoplasms.
Recent reports of the EML4 (echinoderm microtubule-associated protein like 4)-ALK oncoprotein in NSCLC (non-small cell lung cancer), together with the identification of activating point mutations in neuroblastoma, have highlighted ALK as a significant player and target for drug development in cancer.
The case of the anaplastic lymphoma kinase (ALK) nicely exemplifies this, and cell line profiling has revealed that ALK mutations present in a subset of anaplastic large cell lymphomas (ALCLs), non-small cell lung cancers (NSCLCs), and neuroblastomas appear to sensitize cancer cells to treatment with selective ALK kinase inhibitors.
Promising results seen in patients with NSCLC containing fluorescent in situ hybridization-detected ALK rearrangements treated on a phase I study with PF02341066, an oral ALK inhibitor, indicate that ALK represents a new therapeutic target in this molecularly defined subset of NSCLC.
EML4-ALK transcripts (variants 1 and 3) were detected in 9 of 120 NSCLC samples but were not specific for NSCLC since they were also found in non-cancerous lung tissues taken far from the tumor.
EML4-ALK was investigated in 266 resected primary NSCLC, including adenocarcinomas (AD), lymphoepithelioma-like carcinomas, squamous cell carcinomas, mucoepidermoid carcinomas, and adenosquamous carcinomas, by reverse transcriptase-polymerase chain reaction and was verified by sequencing.
In conclusion, anaplastic lymphoma kinase immunoreactivity in non-small cell lung carcinomas was associated with transcriptional up-regulation, ALK locus rearrangement, and the presence of EML4-ALK fusion transcript.
The future value of testing for KRAS mutational status may be to exclude the possibility of an EGFR mutation or anaplastic lymphoma kinase translocation or to identify a molecular subset of patients with NSCLC in whom to pursue a drug development strategy that targets the KRAS pathway.
Genetic rearrangements of the anaplastic lymphoma kinase (ALK) kinase occur in 3% to 13% of non-small cell lung cancer patients and rarely coexist with KRASor EGFR mutations.
The fusion gene EML4-ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene) was recently identified as a novel genetic alteration in non-small-cell lung cancer.
ALK has subsequently been found to be rearranged, mutated, or amplified in a further series of tumours including neuroblastoma, and Non-Small Cell Lung Cancer.
Primary SRC of the lung is a rare subtype of adenocarcinoma, carries a worse prognosis when compared to adenocarcinoma and shares many of the recently identified clinicopathologic characteristics ascribed to EML4-ALK positive non-small cell lung cancer.
After screening tumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial.