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Ref Type Journal Article
PMID (29657135)
Authors Subbiah V, Gainor JF, Rahal R, Brubaker JD, Kim JL, Maynard M, Hu W, Cao Q, Sheets MP, Wilson D, Wilson KJ, DiPietro L, Fleming P, Palmer M, Hu MI, Wirth L, Brose MS, Ou SI, Taylor M, Garralda E, Miller S, Wolf B, Lengauer C, Guzi T, Evans EK
Title Precision Targeted Therapy with BLU-667 for RET-Driven Cancers.
Journal Cancer discovery
Vol 8
Issue 7
Date 2018 Jul
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
BLU-667 BLU667|Pralsetinib RET Inhibitor 39 Pralsetinib (BLU-667) is a small molecule inhibitor that selectively targets activated Ret, which may result in antitumor activity including inhibition of tumor growth and tumor regression (PMID: 29657135, PMID: 32493697).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
RET D631_R635delinsG indel unknown RET D631_R635delinsG results in a deletion of five amino acids in the extracellular domain of the Ret protein from amino acids 631 to 635, combined with the insertion of one glycine (G) at the same site (UniProt.org). D631_R635delinsG has been identified in the scientific literature (PMID: 29657135), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2020).
RET L629P missense unknown RET L629P lies within the extracellular domain of the Ret protein (UniProt.org). L629P has been identified in the scientific literature (PMID: 29657135), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jul 2020).
RET V637R missense unknown RET V637R lies within the transmembrane domain of the Ret protein (UniProt.org). V637R has been identified in the scientific literature (PMID: 29657135), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jul 2020).
RET V804E missense unknown RET V804E lies within the protein kinase domain of the Ret protein (UniProt.org). V804E has been demonstrated to confer drug resistance in the context of a RET fusion in culture (PMID: 29657135), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2020). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET M918T thyroid gland medullary carcinoma predicted - sensitive BLU-667 Phase I Actionable In a Phase I trial, a patient with sporadic medullary thryoid cancer harboring RET M918T demonstrated a partial response, with maximal tumor reduction of 47% following treatment with BLU-667 (PMID: 29657135; NCT03037385). 29657135
RET C634W thyroid gland medullary carcinoma sensitive BLU-667 Preclinical - Cell line xenograft Actionable In a preclinical study, BLU-667 inhibited Ret signaling and proliferation of a medullary thyroid cancer cell line harboring RET C634W in culture, and inhibited tumor growth in xenograft models (PMID: 29657135). detail... 29657135
RET L629P RET D631_R635delinsG RET V637R thyroid gland medullary carcinoma predicted - sensitive BLU-667 Phase I Actionable In a Phase I trial, a patient with medullary thryoid cancer harboring RET D631_R635delinsG, L629P, and V637R demonstrated a partial response, with maximal tumor reduction of 47% at 10 months, following treatment with BLU-667 (PMID: 29657135; NCT03037385). 29657135