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. 797This article is highlighted in the In This Issue feature, p. 781.

• Authors: Vivek Subbiah, Justin F Gainor, Rami Rahal, Jason D Brubaker, Joseph L Kim, Michelle Maynard, Wei Hu, Qiongfang Cao, Michael P Sheets, Douglas Wilson, Kevin J Wilson, Lucian DiPietro, Paul Fleming, Michael Palmer, Mimi I Hu, Lori Wirth, Marcia S Brose, Sai-Hong Ignatius Ou, Matthew Taylor, Elena Garralda, Stephen Miller, Beni Wolf, Christoph Lengauer, Timothy Guzi, Erica K Evans
• Journal: Cancer discovery (Cancer Discov) Vol. 8 Issue 7 Pg. 836-849 (07 2018) ISSN: 2159-8290 [Electronic] United States
• PMID: 29657135 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Pyrazoles
• Pyridines
• Pyrimidines
• pralsetinib
• Proto-Oncogene Proteins c-ret
• RET protein, human

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Carcinoma, Neuroendocrine (drug therapy, genetics, metabolism)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, metabolism)
• Cell Line, Tumor
• Humans
• Lung Neoplasms (drug therapy, genetics, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mutation
• Neoplasms (drug therapy, genetics, metabolism)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-ret (antagonists & inhibitors, genetics, metabolism)
• Pyrazoles (pharmacology, therapeutic use)
• Pyridines (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)
• Thyroid Neoplasms (drug therapy, genetics, metabolism)
• Xenograft Model Antitumor Assays