The tropomyosin receptor kinase (TRK) family, TRKA, TRKB and TRKC are kinases encoded by the genes NTRK1, NTRK2 and NTRK3. Their chromosomal rearrangements with in-frame fusions can cause chimeric TRK fusion proteins to be constitutively activated, which serves as an oncogenic factor by enhancing cell proliferation and tutor cell survival[3]. LOXO-101 sulphate is an orally active highly selective TRK inhibitor that is active against TRKA, TRKB and TRKC with IC50 values below 11 nM[4].
The LOXO-101 inhibited proliferation of Ba/F3 cell expressing the MPRIP-TRKA fusion in a dose dependent manner from 0.1 to 1000 nM after incubating for 72 hours as measured by MTS assay. Moreover, the pTRKA, pAKT and pERK protein expression level measured by western blotting assay of the CUTO-3 lung cancer cells harboring the MPRIP-NTRK1 gene fusion were significantly inhibited after the treatment of 100 - 1000 nM of LOXO-101 sulphate[5].
The mouse model of bone cancer pain was oral administered with 30 mg/kg of LOXO-101. It was found that the treatment could significantly attenuate tumor-induced pain from day 6 - 8 post tumor injection[4].
In a series of phase 1 - 2 clinical trials investigating the safety and efficacy of LOXO-101, 55 patients identified with TRK fusion-positive cancers were enrolled. Their age ranged from 4 months to 76 years. The overall response rate was found to be 75%[6]. At one year, 71% of the responses were ongoing and 55% of the patients have achieved progression-free. Most adverse events were of grade 1 and no patient has discounted because of drug-related adverse events (ClinicalTrials.gov identifier: NCT02122913, NCT02637687, NCT02576431).
Larotrectinib sulfate/硫酸拉曲替尼 细胞实验
Cell Line
Concentration
Treated Time
Description
References
A375 cells
10 µM
16 hours
Larotrectinib enhanced the sensitivity of A375 cells to IFNγ, increasing CXCL10 expression
Nat Immunol. 2024 Feb;25(2):268-281.
SK-MEL-2 cells
10 µM
16 hours
Larotrectinib enhanced the sensitivity of SK-MEL-2 cells to IFNγ, increasing CXCL10 expression
Nat Immunol. 2024 Feb;25(2):268-281.
HEK293 cells
5 µM
2.5 minutes
Assess the uptake of Larotrectinib in HEK293 cells, showing that OATP1A2 increased the uptake of Larotrectinib, while OATP1B1, OATP1B3, and OATP2B1 did not significantly increase its uptake
Br J Pharmacol. 2020 Jul;177(13):3060-3074.
B16 cells
10 µM
24 hours
Larotrectinib enhanced the sensitivity of B16 cells to IFNγ, increasing Stat1 activation and Cxcl10 production
Nat Immunol. 2024 Feb;25(2):268-281.
COLO205 cells
300 nM
24 hours
Lar significantly suppressed the proliferation and migration of COLO205 cells and inhibited the epithelial-mesenchymal transition (EMT) process
J Cell Mol Med. 2022 Nov;26(21):5539-5550.
HCT116 cells
300 nM
24 hours
Lar significantly suppressed the proliferation and migration of HCT116 cells and inhibited the epithelial-mesenchymal transition (EMT) process
J Cell Mol Med. 2022 Nov;26(21):5539-5550.
MDCK-II cells
5 µM
8 hours
Assess the transepithelial transport of Larotrectinib in MDCK-II cells, showing that Larotrectinib was avidly transported by hABCB1 and mAbcg2, and efficiently by hABCG2
Br J Pharmacol. 2020 Jul;177(13):3060-3074.
DU145
20 nM
Overnight
Larotrectinib significantly increased the expression of endogenous AGPS
J Exp Clin Cancer Res. 2024 Jan 11;43(1):16.
22Rv1
20 nM
Overnight
Larotrectinib significantly increased the expression of endogenous AGPS
J Exp Clin Cancer Res. 2024 Jan 11;43(1):16.
Larotrectinib sulfate/硫酸拉曲替尼 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Genetically modified mouse models
Oral
10 mg/kg
Single dose, lasting 8 hours or 1 hour
Assess the pharmacokinetic behavior of Larotrectinib in genetically modified mouse models, showing that ABCB1 and ABCG2 markedly limited the oral availability and brain accumulation of Larotrectinib, and OATP1A/1B and CYP3A also significantly affected its pharmacokinetics
Br J Pharmacol. 2020 Jul;177(13):3060-3074.
Nude mice
HCT116 xenograft model
Intragastrically
20 mg/kg
Twice daily for 3 weeks
Lar significantly reduced tumour volume and weight in the HCT116 xenograft model and activated the AMPK/mTOR signalling pathway
J Cell Mol Med. 2022 Nov;26(21):5539-5550.
Mice
B16 melanoma model
Oral
200 mg/kg
Daily for 60 days
Larotrectinib combined with immunotherapy significantly improved the complete remission rate of melanoma, achieving a CR rate of >60% at the three-month mark, with 40% of animals achieving durable cure
Nat Immunol. 2024 Feb;25(2):268-281.
SCID mice
Subcutaneous tumor xenograft model
Subcutaneous injection
300 mg/kg
Every 24 hours for 28 days
Larotrectinib in combination with ML210 significantly inhibited tumor growth
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