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  • Review Article
  • Published:

Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes

Nature Reviews Clinical Oncology volume 15, pages 151–167 (2018)Cite this article

Subjects

A Corrigendum to this article was published on 28 November 2017

This article has been updated

Key Points

  • Activating alterations of the RET kinase are therapeutically actionable oncogenic drivers across a variety of cancers; in-frame RET rearrangements occur in subsets of non-small-cell lung and papillary thyroid cancers, and germ-line or somatic RET mutations are enriched in medullary thyroid cancers

  • Confirmed and durable responses to multikinase inhibitors with activity against RET can be achieved in a proportion of patients with RET-rearranged or RET-mutant cancers; however, objective response rates are modest

  • The outcomes observed with RET-directed therapy in RET-rearranged or RET-mutant cancers might be explained, in part, by the limitations of multikinase inhibitors, with inhibition of other kinases resulting in 'off-target' toxicities that preclude optimal dosing

  • Novel approaches to RET-directed targeted therapy are currently being explored; potent and specific RET inhibitors with minimal preclinical off-target activity are being evaluated in early stage clinical trials, as are combination therapies

  • Salient to the clinical development of potent RET inhibitors for patients of all ages, selective RET inactivation can affect the nervous, genitourinary, gastrointestinal, and haematopoietic systems during early development, but in adulthood, it leads to mild phenotypes

Abstract

The gene encoding the receptor-tyrosine kinase RET was first discovered more than three decades ago, and activating RET rearrangements and mutations have since been identified as actionable drivers of oncogenesis. Several multikinase inhibitors with activity against RET have been explored in the clinic, and confirmed responses to targeted therapy with these agents have been observed in patients with RET-rearranged lung cancers or RET-mutant thyroid cancers. Nevertheless, response rates to RET-directed therapy are modest compared with those achieved using targeted therapies matched to other oncogenic drivers of solid tumours, such as sensitizing EGFR or BRAFV600E mutations, or ALK or ROS1 rearrangements. To date, no RET-directed targeted therapeutic has received regulatory approval for the treatment of molecularly defined populations of patients with RET-mutant or RET-rearranged solid tumours. In this Review, we discuss how emerging data have informed the debate over whether the limited success of multikinase inhibitors with activity against RET can be attributed to the tractability of RET as a drug target or to the lack, until 2017, of highly specific inhibitors of this oncoprotein in the clinic. We emphasize that novel approaches to targeting RET-dependent tumours are necessary to improve the clinical efficacy of single-agent multikinase inhibition and, thus, hasten approvals of RET-directed targeted therapies.

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Figure 1: Timeline of key developments in therapeutically targeting RET in the clinic.
Figure 2: Mechanisms of RET activation in cancer.
Figure 3: Consequences of inactivating RET mutations or Ret knockout.
Figure 4: Multikinase inhibitor activity against RET and other kinases.
Figure 5: Comparative efficacy of RET-directed targeted therapy in RET-rearranged lung cancers.

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Change history

  • 28 November 2017

    In the online and PDF versions of this Review, in the 'Acquired resistance' subsection, RETI788N was erroneously written as RETI887N, and the ROS1G2032R mutation was written as ROS1D2033N. This information has now been corrected in the online and PDF versions of the Review.

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Acknowledgements

A.D. acknowledges funding support from the NIH (award T32-CA009207). D.S.W.T. acknowledges funding support from the National Medical Research Council (Singapore) Clinician-Scientist Award (NMRC/CSA/007/2016), as well as the Lung Cancer Translational and Clinical Research Flagship Program (NMRC/TCR/007-NCC/2013) The authors would also like to acknowledge Andrew Drilon, who helped design and create Figs 2, 3 and 5 of this article.

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  1. Department of Medicine, Memorial Sloan Kettering Cancer Center, 885 2nd Avenue, New York, 10017, New York, USA

    Alexander Drilon

  2. Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, 10065, New York, USA

    Alexander Drilon

  3. Department of Medicine, Icahn School of Medicine, Mount Sinai Health System, Mount Sinai West, 1000 10th Avenue, New York, 10019, New York, USA

    Zishuo I. Hu

  4. National Cancer Center, 11 Hospital Drive, 169610, Singapore, Singapore

    Gillianne G. Y. Lai & Daniel S. W. Tan

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All authors contributed to researching data for the article, discussions of content, writing the manuscript, and editing and/or reviewing the manuscript before publication.

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Competing interests

A.D. has received honoraria from and has been an advisory board member for Ariad, AstraZeneca, Blueprint Medicines, Exelixis, Genentech/Roche, Ignyta, and Loxo Oncology; he has also received honoraria from Foundation Medicine. The other authors declare no competing interests.

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Drilon, A., Hu, Z., Lai, G. et al. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol 15, 151–167 (2018). https://doi.org/10.1038/nrclinonc.2017.175

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