We sought to develop a pharmacologically advanced inhibitor of the oncoprotein RET. Vepafestinib potently inhibited on-target mutants that confer resistance to approved RET inhibitors while exerting superior efficacy against intracranial disease due to enhanced penetration and retention in the brain.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 digital issues and online access to articles
$119.00 per year
only $9.92 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs43018-023-00631-x/MediaObjects/43018_2023_631_Fig1_HTML.png)
References
Lin, J. J. et al. Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer. Ann Oncol. 31, 1725–1733 (2020). This article is a comprehensive analysis of variable on-target and off-target mechanisms of resistance to RET inhibitors.
Odintsov, I. et al. CIC-mediated modulation of MAPK signaling opposes receptor tyrosine kinase inhibitor response in kinase-addicted sarcoma. Cancer Res. 82, 1110 (2022). This article showed the expression of RET fusion in sarcoma and the efficacy of selpercatinib in preclinical sarcoma models.
Shen, T. et al. The L730V/I RET roof mutations display different activities toward pralsetinib and selpercatinib. NPJ Precis. Oncol. 5, 48 (2021). This article demonstrates that ‘rooftop’ RET L730V and L730I substitutions confer resistance to RET inhibitors.
Colclough, N. et al. Preclinical comparison of the blood-brain barrier permeability of osimertinib with other EGFR TKIs. Clin. Cancer Res. 27, 189–201 (2021). This article presents preclinical evidence of the superior brain penetrability of osimertinib and demonstrates the link between low in vitro transporter efflux ratios and increased brain penetrance in vivo.
Wu, Y. L. et al. Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N. Engl. J. Med. 383, 1711–1723 (2020). This article reports the clinical efficacy of osimertinib, including intracranial activity.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This is a summary of: Miyazaki, I. et al. Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations. Nat. Cancer https://doi.org/10.1038/s43018-023-00630-y (2023).
Rights and permissions
About this article
Cite this article
Vepafestinib: a RET-selective inhibitor with enhanced CNS penetrance targets therapy-resistant mutants. Nat Cancer 4, 1220–1221 (2023). https://doi.org/10.1038/s43018-023-00631-x
Published:
Issue Date:
DOI: https://doi.org/10.1038/s43018-023-00631-x
This article is cited by
-
The never-abating excitement for targeted therapies
Nature Cancer (2023)