LOXO-101 (Larotrectinib) sulfate is orally available, ATP-competitive pan-TRK inhibitor, with IC50 values of 0.9nM and 2.8nM for TRKA and TRKC, respectively [1]. LOXO-101 sulfate preferentially blocks the ATP-binding site of TRKA, TRKB, and TRKC, thereby inhibiting the TRK catalytic activity, the autophosphorylation, and the activation of downstream pathways [2]. LOXO-101 sulfate has been widely used in preclinical models to inhibit tumor growth[3].
In vitro, LOXO-101 sulfate treatment for 72 hours significantly inhibited the proliferation of CUTO-3.29 cells, KM12 cells and MO-91 cells, with IC50 values of 59nM, 3.5nM and 1nM, respectively[4]. Treatment with 300nM LOXO-101 sulfate for 24 hours significantly upregulated the expression of the epithelial marker E-cadherin in HCT116 cells, decreased the expression of mesenchymal markers (including vimentin and MMP2), and inhibited cell migration[5]. Treatment of T98G cells with 1μM LOXO-101 sulfate for 24 hours induced apoptosis, disrupted mitochondrial membrane potential and upregulated the activities of caspase 3, 8 and 9[6].
In vivo, LOXO-101 sulfate treatment via oral administration at a dose of 200mg/kg/day for 6 weeks significantly reduced the levels of leukemic infiltration in the bone marrow and spleen of the patient-derived xenograft (PDX) mouse model of ETV6-NTRK3 [7]. Oral administration of LOXO-101 sulfate (50mg/kg) three times a week for 5 weeks can significantly inhibit the growth of tumors in a 143B/NGF (overexpressed NGF) cell-xenograft mouse model, without affecting the weight of the mice[8].
References:
[1] Drilon A, Nagasubramanian R, Blake J F, et al. A next-generation TRK kinase inhibitor overcomes acquired resistance to prior TRK kinase inhibition in patients with TRK fusion–positive solid tumors[J]. Cancer discovery, 2017, 7(9): 963-972.
[2] Berger S, Martens U M, Bochum S. Larotrectinib (LOXO-101)[J]. Small Molecules in Oncology, 2018: 141-151.
[3] Hong D S, Brose M S, Doebele R C, et al. Abstract PR13: Clinical safety and activity from a phase 1 study of LOXO-101, a selective TRKA/B/C inhibitor, in solid-tumor patients with NTRK gene fusions[J]. Molecular Cancer Therapeutics, 2015, 14(12_Supplement_2): PR13-PR13.
[4] Doebele R C, Davis L E, Vaishnavi A, et al. An oncogenic NTRK fusion in a patient with soft-tissue sarcoma with response to the tropomyosin-related kinase inhibitor LOXO-101[J]. Cancer discovery, 2015, 5(10): 1049-1057.
[5] Kong W, Zhu H, Zheng S, et al. Larotrectinib induces autophagic cell death through AMPK/mTOR signalling in colon cancer[J]. Journal of cellular and molecular medicine, 2022, 26(21): 5539-5550.
[6] Zając A, Sumorek-Wiadro J, Maciejczyk A, et al. The engagement of Ras/Raf/MEK/ERK and PLCγ1/PKC pathways regulated by TrkB receptor in resistance of glioma cells to elimination upon apoptosis induction[J]. Neuropharmacology, 2025, 262: 110204.
[7] Roberts K G, Bridges O, Janke L J, et al. Genetic Modeling and Therapeutic Targeting of ETV6-NTRK3 with Loxo-101in Acute Lymphoblastic Leukemia[J]. Blood, 2016, 128(22): 278.
[8] Hou C H, Chen W L, Lin C Y. Targeting nerve growth factor-mediated osteosarcoma metastasis: mechanistic insights and therapeutic opportunities using larotrectinib[J]. Cell Death & Disease, 2024, 15(5): 381.
LOXO-101 (Larotrectinib) sulfate是一种口服可用的ATP竞争性泛TRK抑制剂，对TRKA和TRKC的IC50值分别为0.9nM和2.8nM[1]。LOXO-101 sulfate优先阻断TRKA、TRKB和TRKC的ATP结合位点，从而抑制TRK催化活性、自磷酸化及下游通路的激活[2]。LOXO-101 sulfate已被广泛用于临床前模型以抑制肿瘤生长[3]。
在体外，LOXO-101 sulfate处理72小时显著抑制了CUTO-3.29细胞、KM12细胞和MO-91细胞的增殖，IC50值分别为59nM、3.5nM和1nM[4]。使用300nM的LOXO-101 sulfate处理24小时，显著上调了HCT116细胞中上皮标志物E-cadherin的表达，降低了间充质标志物（包括vimentin和MMP2）的表达，并抑制了细胞迁移[5]。使用1µM的LOXO-101 sulfate处理T98G细胞24小时，诱导了细胞凋亡，破坏了线粒体膜电位，并上调了caspase 3、8和9的活性[6]。
在体内，每日口服给予200mg/kg/day的LOXO-101 sulfate，持续6周，显著降低了ETV6-NTRK3患者来源异种移植（PDX）小鼠模型中骨髓和脾脏的白血病浸润水平[7]。每周三次口服给予LOXO-101 sulfate（50mg/kg），持续5周，可显著抑制143B/NGF（过表达NGF）细胞异种移植小鼠模型中的肿瘤生长，且不影响小鼠的体重[8]。