The biology and treatment of EML4-ALK non-small cell lung cancer

Abstract

The fusion between echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) has recently been identified in a subset of non-small cell lung cancers (NSCLCs). EML4-ALK is most often detected in never smokers with lung cancer and has unique pathologic features. EML4-ALK is oncogenic both in vitro and in vivo and ALK kinase inhibitors are quite effective in pre-clinical model systems. More recently ALK inhibitors have entered clinical development and remarkably clinical efficacy has been observed in NSCLC patients harbouring EML4-ALK translocations. This review will focus on the biology, clinical characteristics, diagnosis and treatment of EML4-ALK NSCLC.

Figure 1. Frequency of somatic genetic changes in NSCLC

A. EML4-ALK translocations, EGFR, KRAS and ERBB2 mutation frequencies broken down by smoking history. B. Frequency of somatic mutations in never or former light (≤ 10 pack years; quit ≥ 1 year ago) smokers. Data obtained from –. Of note the somewhat higher EGFR mutation frequency is likely a reflection of the predominance of studies from East Asian countries. The EGFR mutation frequency in Caucasian never/former light smokers is ~ 35%.

Figure 2. Pathologic characteristics of EML4-ALK NSCLC

EML4-ALK NSCLC demonstrate a signet cell features (arrow). A. 40×X magnification B. 1000 ×X magnification.

Figure 3. Different variants of EML4-ALK and non-EML4 fusion partners

A. Different variants of EML4-ALK are depicted. The nomenclature refers to the exon in EML4 translocated to the exon in ALK. B. Frequency of different EML4-ALK variants. The most common variants are E13;A20 (variant 1) and E6a/b; A20 (variant 3). Data obtained from –, , –. Of note not all studies list the specific EML4-ALK variant.

Figure 4. Diagnostic methods for EML4-ALK NSCLC

A. FISH analysis using the ALK split apart probe. The arrows depict the split signals indicative of a chromosome 2 inversion. The tumor is heterozygous – the signals remain together on the other allele. B. IHC analysis for ALK using the D5F3 (Cell Signaling Technology 41) antibody. Shown are examples of low (left) and high (right) ALK expressing tumors.