ROS1-dependent cancers — biology, diagnostics and therapeutics

Abstract

The proto-oncogene ROS1 encodes a receptor tyrosine kinase with an unknown physiological role in humans. Somatic chromosomal fusions involving ROS1 produce 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 of ROS1 fusion-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 that ROS1 fusions present and the strategies to target ROS1 fusion proteins in both treatment-naive and acquired-resistance settings. ROS1 fusions 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 identifying ROS1 fusions and the current therapeutic concepts relating to ROS1 fusion-positive cancers, including the resistance mechanisms that have emerged with current ROS1 inhibitors. The proto-oncogene ROS1 encodes the receptor tyrosine kinase ROS1 with an unclear physiological role in humans. Chromosomal rearrangement resulting in ROS1 fusion is the main mechanism underlying ROS1-driven oncogenesis. Most ROS1 mutations have unknown significance, and deregulated ROS1 expression is probably, at most, a secondary oncogenic mediator. ROS1 fusions can be challenging to detect. Whereas no diagnostic assay is without limitations, the use of complementary DNA-based and RNA-based sequencing assays can maximize the identification of ROS1 fusions; immunohistochemistry is a proposed screening assay. Cancers with diverse cellular origins can be driven by ROS1 fusions in both adults and children; however, ROS1 inhibitors are only approved for ROS1 fusion-positive non-small-cell lung cancers and have yet to receive a histology-agnostic indication. The spectrum of ROS1-dependent and/or ROS1-independent resistance can be influenced by the subcellular localization of the fusion protein, the mode of drug binding (type I versus type II) and the profile of non-ROS1-kinase inhibition. The contribution of polyclonality to ROS1 inhibitor resistance remains underexplored.