A lung cancer cell line expressing endogenous variant 3 of EML4-ALK underwent cell death on exposure to a specific inhibitor of ALK catalytic activity.
One of the most recent targets is microtubule-associated human EML4 generating a fusion-type oncogene with ALK demonstrating marked transforming activity in lung cancer.
More recently, a surprising positive effect of an ALK inhibitor on EML4-ALK-positive lung cancer has been suggested that lung cancer in never smokers is likely to be an assemblage of molecularly defined subsets which would be a good candidate for personalized diagnostic and therapeutic approaches.
Similar levels of drug sensitivity were displayed by the three most common ALK fusion proteins in lung cancer (EML4-ALK variants E13;A20, E20;A20, and E6b;A20) as well as a KIF5B-ALK fusion protein.
These observations indicate that signals from oncogenic drivers (EGFR signaling in EGFR -mutant lung cancer and ALK signaling in EML4-ALK lung cancer) and ligand-triggered bypass signals (HGF-Met and EGFR ligands-EGFR, respectively) must be simultaneously blocked to avoid the resistance.
The discovery of the chromosomal fusion product of anaplastic lymphoma kinase (ALK) with echinoderm microtubule-associated protein-like 4 (EML4) (EML4-ALK) has changed the treatment paradigm of lung cancer.
Combined TAE684 with PI3K inhibitor synergistically inhibited the proliferation of EML4-ALK-positive cells in vitro and significantly suppressed the growth of H2228 xenografts in vivo, suggesting the potential clinical application of such combinatorial therapy regimens in patients with EML4-ALK positive lung cancer.
Although there is a possibility that the left lung cancer is de novo one with multiple metastases, detection of the same fusion gene of the very rare EML4-ALK variant 1 in both tumors suggests that the left cancer is a recurrence of the right lung cancer after an interval of 15 years.
Examples of these molecularly targeted biomarker therapies are: tyrosine kinase inhibitors in chronic myeloid leukemia and gastrointestinal tumors; anaplastic lymphoma kinase (ALK) inhibitors in lung cancer with EML4-ALk fusion; HER2/neu blockage in HER2/neu-positive breast cancer; and epidermal growth factor receptors (EGFR) inhibition in EGFR-mutated lung cancer.
Our in vivo imaging models of multiple organ sites may provide useful resources to analyze further the pathogenesis of EML4-ALK lung cancer and its response and resistance to ALK inhibitors in various organ microenvironments.