Pralsetinib (Blu667) is a selective inhibitor of the rearranged during transfection (RET) kinase, indicated for the treatment of certain RET-altered positive tumors[1-2]. By selectively inhibiting RET fusions and mutations, Pralsetinib blocks downstream signaling pathways such as MAPK and PI3K-AKT, thereby suppressing tumor cell proliferation and inducing apoptosis[3-4].
In vitro, treatment of RET-altered thyroid cancer and non-small cell lung cancer cells (TPC1, LC-2/ad, TT, and MZCRC1) with Pralsetinib (2-5µM) significantly inhibited cell proliferation and induced cell death[5]. In T47D and MCF7 breast cancer cells expressing transcriptionally active ESR1 fusion proteins or ERα ligand-binding domain point mutations (Y537S, D538G), Pralsetinib (100-500nM) markedly suppressed cell growth[6].
In vivo, daily oral administration of Pralsetinib (10-30mg/kg) in female athymic nude mice intracranially inoculated with MDA-MB-231-BrM triple-negative breast cancer cells. Pralsetinib significantly inhibited intracranial tumor growth[7]. In a C57BL/6 mouse model bearing orthotopic lung adenocarcinoma tumors derived from Trim24-Ret cell lines, daily oral treatment with Pralsetinib (20mg/kg) for 8 weeks induced significant tumor shrinkage, although acquired resistance emerged after 3 weeks of treatment[8].
References:
[1] Markham A. Pralsetinib: First Approval. Drugs. 2020 Nov;80(17):1865-1870.
[2] Nguyen L, Monestime S. Pralsetinib: Treatment of metastatic RET fusion-positive non-small cell lung cancer. Am J Health Syst Pharm. 2022 Mar 21;79(7):527-533
[3] Syed YY. Pralsetinib: A Review in Advanced RET Fusion-Positive NSCLC. Drugs. 2022 May;82(7):811-816.
[4] Griesinger F, Curigliano G, Thomas M, et al. Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial. Ann Oncol. 2022 Nov;33(11):1168-1178.
[5] Hu X, Liu X, Khatri U, et al. The heterogeneous transition state of resistance to RET kinase inhibitors converges on ERK1/2-driven Aurora A/B kinases. Drug Resist Updat. 2023 May;68:100958.
[6] Gou X, Kim BJ, Anurag M, et al. Kinome Reprogramming Is a Targetable Vulnerability in ESR1 Fusion-Driven Breast Cancer. Cancer Res. 2023 Oct 2;83(19):3237-3251.
[7] Regua AT, Bindal S, Najjar M, et al. RET Receptor Tyrosine Kinase Promotes Breast Cancer Metastasis to the Brain and RET Inhibitors Pralsetinib and Selpercatinib Suppress Breast Cancer Brain Metastases. bioRxiv [Preprint]. 2025 Oct 8:2025.10.07.680986.
[8] Hinz TK, Le AT, Doan T, et al. Modeling acquired TKI resistance and effective combination therapeutic strategies in murine RET+ lung adenocarcinoma. bioRxiv [Preprint]. 2025 Jun 7:2025.06.04.657911.
Pralsetinib (Blu667)是转染重排（RET）激酶抑制剂，用于治疗特定的RET基因变异阳性肿瘤[1-2]。Pralsetinib通过选择性抑制RET融合和突变，阻断下游MAPK、PI3K-AKT等信号通路，从而抑制肿瘤细胞增殖并诱导其凋亡[3-4]。
在体外，Pralsetinib（2-5μM）处理RET基因改变的TPC1、LC-2/ad、TT和MZCRC1甲状腺癌和非小细胞肺癌细胞，Pralsetinib显著抑制细胞增殖并诱导细胞死亡[5]。Pralsetinib（100-500nM）处理表达转录活性ESR1融合蛋白或ERα配体结合域点突变（Y537S、D538G）的T47D和MCF7乳腺癌细胞，Pralsetinib显著抑制细胞生长[6]。
在体内，Pralsetinib（10-30mg/kg；每日一次口服给药）处理经颅内接种MDA-MB-231-BrM三阴性乳腺癌细胞的雌性无胸腺裸鼠，显著抑制脑内肿瘤生长[7]。Pralsetinib（20mg/kg；每日一次口服给药）处理Trim24-Ret细胞系肺腺癌原位移植瘤的C57BL/6小鼠8周，Pralsetinib显著诱导肿瘤缩小，但治疗3周后出现获得性耐药[8]。