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).
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