Precision targeted therapy with BLU-667 for RET-driven cancers

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 & 5 others Stephen Miller, Beni Wolf, Christoph Lengauer, Timothy Guzi, Erica K. Evans

    Research output: Contribution to journalArticle

    28 Citations (Scopus)

    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.

    Original languageEnglish (US)
    Pages (from-to)836-849
    Number of pages14
    JournalCancer Discovery
    Volume8
    Issue number7
    DOIs
    StatePublished - Jul 1 2018

    Fingerprint

    Transfection
    Neoplasms
    Thyroid Neoplasms
    Therapeutics
    Non-Small Cell Lung Carcinoma
    Mutation
    Receptor Protein-Tyrosine Kinases
    Heterografts

    ASJC Scopus subject areas

    • Oncology

    Cite this

    Subbiah, V., Gainor, J. F., Rahal, R., Brubaker, J. D., Kim, J. L., Maynard, M., ... Evans, E. K. (2018). Precision targeted therapy with BLU-667 for RET-driven cancers. Cancer Discovery, 8(7), 836-849. https://doi.org/10.1158/2159-8290.CD-18-0338

    Precision targeted therapy with BLU-667 for RET-driven cancers. / Subbiah, Vivek; Gainor, Justin F.; Rahal, Rami; Brubaker, Jason D.; Kim, Joseph L.; Maynard, Michelle; Hu, Wei; Cao, Qiongfang; Sheets, Michael P.; Wilson, Douglas; Wilson, Kevin J.; Dipietro, Lucian; Fleming, Paul; Palmer, Michael; Hu, Mimi I.; Wirth, Lori; Brose, Marcia S.; Ou, Sai Hong Ignatius; Taylor, Matthew; Garralda, Elena; Miller, Stephen; Wolf, Beni; Lengauer, Christoph; Guzi, Timothy; Evans, Erica K.

    In: Cancer Discovery, Vol. 8, No. 7, 01.07.2018, p. 836-849.

    Research output: Contribution to journalArticle

    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, SHI, Taylor, M, Garralda, E, Miller, S, Wolf, B, Lengauer, C, Guzi, T & Evans, EK 2018, 'Precision targeted therapy with BLU-667 for RET-driven cancers', Cancer Discovery, vol. 8, no. 7, pp. 836-849. https://doi.org/10.1158/2159-8290.CD-18-0338
    Subbiah V, Gainor JF, Rahal R, Brubaker JD, Kim JL, Maynard M et al. Precision targeted therapy with BLU-667 for RET-driven cancers. Cancer Discovery. 2018 Jul 1;8(7):836-849. https://doi.org/10.1158/2159-8290.CD-18-0338
    Subbiah, Vivek ; Gainor, Justin F. ; Rahal, Rami ; Brubaker, Jason D. ; Kim, Joseph L. ; Maynard, Michelle ; Hu, Wei ; Cao, Qiongfang ; Sheets, Michael P. ; Wilson, Douglas ; Wilson, Kevin J. ; Dipietro, Lucian ; Fleming, Paul ; Palmer, Michael ; Hu, Mimi I. ; Wirth, Lori ; Brose, Marcia S. ; Ou, Sai Hong Ignatius ; Taylor, Matthew ; Garralda, Elena ; Miller, Stephen ; Wolf, Beni ; Lengauer, Christoph ; Guzi, Timothy ; Evans, Erica K. / Precision targeted therapy with BLU-667 for RET-driven cancers. In: Cancer Discovery. 2018 ; Vol. 8, No. 7. pp. 836-849.
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    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.",
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    AU - Kim, Joseph L.

    AU - Maynard, Michelle

    AU - Hu, Wei

    AU - Cao, Qiongfang

    AU - Sheets, Michael P.

    AU - Wilson, Douglas

    AU - Wilson, Kevin J.

    AU - Dipietro, Lucian

    AU - Fleming, Paul

    AU - Palmer, Michael

    AU - Hu, Mimi I.

    AU - Wirth, Lori

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    AU - Ou, Sai Hong Ignatius

    AU - Taylor, Matthew

    AU - Garralda, Elena

    AU - Miller, Stephen

    AU - Wolf, Beni

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