ROS1 Rearrangements in Lung Cancer: A Rare but Targetable Driver

The Fusion and Its Effect

A rearrangement fuses the kinase region of ROS1 to a partner gene, most often CD74, EZR, SDC4 or SLC34A2. The fusion protein is constitutively active and signals through the RAS-MAPK, PI3K and JAK-STAT pathways.

ROS1 has no known physiological ligand in humans, so the fusion represents a gain of a new oncogenic activity rather than amplification of a normal one.

Relationship to ALK

ROS1 and ALK kinase domains share substantial sequence similarity, which is why crizotinib, entrectinib and lorlatinib have activity against both. However, some ALK-selective drugs such as alectinib are not active against ROS1.

The genes are separate and a tumour is tested for each; a positive ALK result does not imply anything about ROS1 and vice versa.

Detection

ROS1 immunohistochemistry is a sensitive screen but has lower specificity than for ALK, so positive results are typically confirmed by fluorescence in-situ hybridisation or by RNA-based next-generation sequencing.

RNA sequencing is well suited to ROS1 because the many possible partners and breakpoints are hard to capture with DNA panels alone.

Treatment and Resistance

Crizotinib and entrectinib are established first-line options, with entrectinib and lorlatinib offering better central-nervous-system coverage. Repotrectinib is a newer ROS1 inhibitor designed to retain activity against common resistance mutations.

The ROS1 G2032R solvent-front mutation is a frequent cause of acquired resistance and is not covered by crizotinib or entrectinib, which influences the choice of later therapy.

Interpretation Notes

A ROS1 report should state the confirmation method and, where available, the fusion partner. An immunohistochemistry-only positive is usually considered provisional until confirmed.

ROS1 fusions are generally mutually exclusive with other lung-cancer drivers.

Key Takeaways

• ·ROS1 fusions occur in 1 to 2 percent of non-small-cell lung cancers and create a constitutively active kinase.
• ·ROS1 resembles ALK, and several drugs cover both, but it is a separate gene tested separately.
• ·ROS1 immunohistochemistry needs confirmation by FISH or RNA sequencing.
• ·The G2032R mutation drives resistance to crizotinib and entrectinib; repotrectinib targets it.