EML4-ALK translocation may be associated with resistance to EGFR-TKI, and EGFR signaling may contribute to resistance to ALK inhibitor in EML4-ALK-positive NSCLC.
Although the major known fusion partner for ALK in NSCLC is the Echinoderm microtubule-associated protein-like 4 (EML4), of which a minimum of 15 variants have been described, an additional 20 further ALK fusion variants with other genes are known, of which three have already been found in NSCLC.
This study suggests that EGFR kinase domain mutations and EML4-ALK translocations are radiosensitive NSCLC genotypes, and proposes a novel model to identify radiosensitive subtypes of NSCLC.
While understanding molecular mechanisms of resistance is critical to overcome therapeutic resistance, understanding physiologic mechanisms of resistance through analyzing anatomic patterns of failure may be equally crucial to improve long-term survival for patients with EML4-ALK translocation positive NSCLC.
Echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) gene rearrangements and epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) have been intensively studied.
We investigated ALK and EML4 gene aberrations (amplifications, translocations, inversions) by fluorescent in situ hybridization (FISH) (n=175) and ALK and EML4 protein expression by immunohistochemistry (n=221) in NSCLC BM and corresponding primary tumors.
Here, we identified CH5424802, a potent, selective, and orally available ALK inhibitor with a unique chemical scaffold, showing preferential antitumor activity against cancers with gene alterations of ALK, such as nonsmall cell lung cancer (NSCLC) cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma (ALCL) cells expressing NPM-ALK fusion in vitro and in vivo.
Malignant pleural effusion cell blocks are substitutes for tissue in EML4-ALK rearrangement detection in patients with advanced non-small-cell lung cancer.
The coexistence of EGFR and ALK-EML4 gene mutations represents a rare event (about 1%) in patients with non small cell lung cancer (NSCLC) and the few cases described in the literature have all been treated by different methods.
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.
NSCLC cell lines (n = 8) with known oncogenic backgrounds (K-Ras, EGFR and EML4-ALK) were exposed to several kinase inhibitors and analyzed for cell growth/cytotoxicity and signaling.
We also verified results in samples from 62 patients with untreated NSCLC and detected a correlation between LAG-3 expression and EGFR and KRAS mutation and echinoderm microtubule associated protein like 4 gene (EML4)-anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangement.