ROS1-dependent cancers - biology, diagnostics and therapeutics

The proto-oncogeneROS1encodes a receptor tyrosine kinase with an unknown physiological role in humans. Somatic chromosomal fusions involvingROS1produce chimeric oncoproteins that drive a diverse range of cancers in adult and paediatric patients. ROS1-directed tyrosine kinase inhibitors (TKIs) are therapeutically active against these cancers, although only early-generation multikinase inhibitors have been granted regulatory approval, specifically for the treatment ofROS1fusion-positive non-small-cell lung cancers; histology-agnostic approvals have yet to be granted. Intrinsic or extrinsic mechanisms of resistance to ROS1 TKIs can emerge in patients. Potential factors that influence resistance acquisition include the subcellular localization of the particular ROS1 oncoprotein and the TKI properties such as the preferential kinase conformation engaged and the spectrum of targets beyond ROS1. Importantly, the polyclonal nature of resistance remains underexplored. Higher-affinity next-generation ROS1 TKIs developed to have improved intracranial activity and to mitigate ROS1-intrinsic resistance mechanisms have demonstrated clinical efficacy in these regards, thus highlighting the utility of sequential ROS1 TKI therapy. Selective ROS1 inhibitors have yet to be developed, and thus the specific adverse effects of ROS1 inhibition cannot be deconvoluted from the toxicity profiles of the available multikinase inhibitors. Herein, we discuss the non-malignant and malignant biology of ROS1, the diagnostic challenges thatROS1fusions present and the strategies to target ROS1 fusion proteins in both treatment-naive and acquired-resistance settings. ROS1fusions can be identified across a range of malignancies and confer a high level of sensitivity to ROS1 tyrosine kinase inhibitors. Herein, the authors discuss the non-malignant and malignant biology of ROS1, the diagnostic approaches to identifyingROS1fusions and the current therapeutic concepts relating toROS1fusion-positive cancers, including the resistance mechanisms that have emerged with current ROS1 inhibitors.

Automated summary

The proto-oncogene ROS1 encodes a receptor tyrosine kinase without a well-defined physiological role, and somatic chromosomal fusions involving ROS1 lead to chimeric oncoproteins that drive various cancers. Although ROS1-directed tyrosine kinase inhibitors show therapeutic efficacy, resistance mechanisms remain unclear.