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Precision Targeted Therapy with BLU-667 for RET-Driven Cancers
Abstract
The receptor tyrosine kinase rearranged during transfection (RET) is an oncogenic driver activated in multiple cancers, including non–small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and papillary thyroid cancer. No approved therapies have been designed to target RET; treatment has been limited to multikinase inhibitors (MKI), which can have significant off-target toxicities and limited efficacy. BLU-667 is a highly potent and selective RET inhibitor designed to overcome these limitations. In vitro, BLU-667 demonstrated ≥10-fold increased potency over approved MKIs against oncogenic RET variants and resistance mutants. In vivo, BLU-667 potently inhibited growth of NSCLC and thyroid cancer xenografts driven by various RET mutations and fusions without inhibiting VEGFR2. In first-in-human testing, BLU-667 significantly inhibited RET signaling and induced durable clinical responses in patients with RET-altered NSCLC and MTC without notable off-target toxicity, providing clinical validation for selective RET targeting. Significance: Patients with RET-driven cancers derive limited benefit from available MKIs. BLU-667 is a potent and selective RET inhibitor that induces tumor regression in cancer models with RET mutations and fusions. BLU-667 attenuated RET signaling and produced durable clinical responses in patients with RET-altered tumors, clinically validating selective RET targeting. Cancer Discov; 8(7); 836–49. ©2018 AACR. See related commentary by Iams and Lovly, p. 797. This article is highlighted in the In This Issue feature, p. 781
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Metadata
- Authors
- Subbiah, V., Gainor, J. F., Rahal, R., Brubaker, J. D., Kim, J. L., Maynard, M., Hu, W., Cao, Q., Sheets, M. P., Wilson, D., Wilson, K. J., DiPietro, L., Fleming, P., Palmer, M., Hu, M. I., Wirth, L., Brose, M. S., Ou, S.-H. I., Taylor, M., Garralda, E., Miller, S., Wolf, B., Lengauer, C., Guzi, T., & Evans, E. K.
- Venue
- Cancer Discovery
- Published
- 2018-07-01
- Volume
- 8
- Issue
- 7
- Pages
- 836-849
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W2797098362
- Cited by
- 396
- References
- 41
- FWCI
- 33.65
- Type
- journal article
- Language
- en
- Open access
- closed
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- Subbiah, V., Gainor, J. F., Rahal, R., Brubaker, J. D., Kim, J. L., Maynard, M., Hu, W., Cao, Q., Sheets, M. P., Wilson, D., Wilson, K. J., DiPietro, L., Fleming, P., Palmer, M., Hu, M. I., Wirth, L., Brose, M. S., Ou, S.-H. I., Taylor, M., . . . Evans, E. K. (2018). Precision Targeted Therapy with BLU-667 for RET-Driven Cancers. Cancer Discovery. https://doi.org/10.1158/2159-8290.cd-18-0338
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