ALK Rearrangements in Lung Cancer: Fusions and Their Inhibitors

What an ALK Fusion Is

A chromosomal rearrangement joins the 3' part of ALK, containing the kinase domain, to the 5' part of a partner gene. In lung cancer the most common partner is EML4, and several EML4-ALK variants exist depending on the breakpoint.

The partner provides a promoter and often a dimerisation domain, so the fusion protein is expressed constantly and the kinase is switched on without a ligand.

Who Has It

ALK rearrangements are found in roughly 3 to 5 percent of non-small-cell lung cancers, typically adenocarcinoma, and are enriched in younger patients and never- or light-smokers.

They are essentially always mutually exclusive with EGFR and KRAS mutations.

Detection Methods

ALK status can be assessed by fluorescence in-situ hybridisation (break-apart probes), by immunohistochemistry for the abnormally expressed ALK protein, by RNA-based next-generation sequencing, or by DNA sequencing that covers the intronic breakpoints.

Immunohistochemistry is a good screen; RNA sequencing is particularly useful because DNA panels can miss fusions with breakpoints in large introns.

Generations of Inhibitors

Crizotinib was the first ALK inhibitor. Second-generation agents (alectinib, brigatinib, ceritinib) are more potent, have better central-nervous-system activity, and are now common first-line choices. Lorlatinib, a third-generation inhibitor, covers many resistance mutations and has strong brain penetration.

Resistance arises through secondary ALK kinase-domain mutations, ALK copy-number gain, or activation of bypass pathways; the pattern helps guide the next inhibitor.

Interpretation Notes

A positive ALK result should state the method and, where known, the fusion partner and variant, since some EML4-ALK variants are associated with different durability of response.

A single negative assay with limited breakpoint coverage does not completely exclude a fusion when clinical suspicion is high.

Key Takeaways

• ·ALK fusions (commonly EML4-ALK) create a constitutively active kinase driver.
• ·They occur in 3 to 5 percent of non-small-cell lung cancers, often in never-smokers.
• ·Detection uses FISH, immunohistochemistry, or RNA/DNA sequencing, each with trade-offs.
• ·Second- and third-generation inhibitors (alectinib, lorlatinib) address resistance and brain disease.