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ROS1-dependent cancers — biology, diagnostics and therapeutics

Nature Reviews Clinical Oncology volume 18, pages 35–55 (2021)Cite this article

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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.

Key points

  • 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.

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Fig. 1: ROS1 gene, structure and signalling.
Fig. 2: ROS1 fusion structure and cellular location.
Fig. 3: Mechanisms of resistance to ROS1 TKIs.
Fig. 4: Preclinical activity and binding modes of ROS1 TKIs.
Fig. 5: Clinical activity of ROS1 TKIs and potential treatment algorithm for ROS1-rearranged cancers.
Fig. 6: ROS1 expression and ROS1 inhibitor safety profile.

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Acknowledgements

The authors would like to thank Dr Clare Wilhelm for critically reading the manuscript and for editorial contributions. The work of the authors is supported in part by NIH grants (P01 CA129243 and P30 CA008748 to A.D. and R01 CA233495-01A1 to M.A.D.) and an American Cancer Society (ACS) grant (RSG-19-082-01-TBG to M.A.D.).

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Authors and Affiliations

  1. Early Drug Development and Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Alexander Drilon & Adam Schoenfeld

  2. Department of Medicine, Weill Cornell Medical College, New York, NY, USA

    Alexander Drilon & Adam Schoenfeld

  3. Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA

    Chelsea Jenkins, Sudarshan Iyer, Clare Keddy & Monika A. Davare

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Contributions

All authors researched the data for the article. A.D., C.K. and M.A.D. made substantial contributions to discussions of content. A.D., C.J., S.I., A.S. and M.A.D. wrote the manuscript, and A.D. and M.A.D. reviewed/edited the manuscript before submission.

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Correspondence to Alexander Drilon or Monika A. Davare.

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Competing interests

A.D. has received honoraria from or participated on the advisory boards of 14ner/Elevation Oncology, Abbvie, ArcherDX, AstraZeneca, Beigene, BergenBio, Blueprint Medicines, Exelixis, Helsinn, Hengrui Therapeutics, Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Monopteros, MORE Health, Pfizer, Remedica, Takeda/Ariad/Millenium, TP Therapeutics, Tyra Biosciences and Verastem; research support paid to his institution from Exelixis, GlaxoSmithKlein, Pfizer, PharmaMar, Taiho and Teva; research support from Foundation Medicine; personal fees from Boehringer Ingelheim, Merck, Merus and Puma; and CME honoraria from Axis, Medscape, OncLive, Paradigm Medical Communications, Peerview Institute, PeerVoice, Physicians Education Resources, Research to Practice, Targeted Oncology and WebMD. The other authors declare no competing interests.

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Nature Reviews Clinical Oncology thanks Myung-Ju Ahn, Luc Friboulet, who co-reviewed with Francesco Facchinetti, Justin Gainor and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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GTEx Portal: https://gtexportal.org/home/

MatchMaker: https://www.cgl.ucsf.edu/chimera/docs/ContributedSoftware/matchmaker/matchmaker.html

RCSB PDB 3ZBF: https://www.rcsb.org/structure/3ZBF

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Drilon, A., Jenkins, C., Iyer, S. et al. ROS1-dependent cancers — biology, diagnostics and therapeutics. Nat Rev Clin Oncol 18, 35–55 (2021). https://doi.org/10.1038/s41571-020-0408-9

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