Zurletrectinib is a next-generation TRK inhibitor with strong intracranial activity against NTRK fusion-positive tumours with on-target resistance to first-generation agents Journal Article
| Authors: | Roa, P.; Foglizzo, V.; Harada, G.; Repetto, M.; Kulick, A.; de Stanchina, E.; de Marchena, M.; Auwardt, S.; Sayed Ahmed, S.; Bremer, N. V.; Yang, S. R.; Feng, Y.; Zhou, C.; Kong, N.; Liang, R.; Xu, H.; Zhang, B.; Bardelli, A.; Toska, E.; Ventura, A.; Drilon, A.; Cocco, E. |
| Article Title: | Zurletrectinib is a next-generation TRK inhibitor with strong intracranial activity against NTRK fusion-positive tumours with on-target resistance to first-generation agents |
| Abstract: | Background: While NTRK fusion-positive cancers can be exquisitely sensitive to first-generation TRK inhibitors, resistance inevitably occurs, mediated in many cases by acquired NTRK mutations. Next-generation inhibitors (e.g., selitrectinib, repotrectinib) maintain activity against these TRK mutant tumors; however, there are no next-generation TRK inhibitors approved by the FDA and select trials have stopped treating patients. Thus, the identification of novel, potent and specific next-generation TRK inhibitors is a high priority. Methods: In silico modeling and in vitro kinase assays were performed on TRK wild type (WT) and TRK mutant kinases. Cell viability and clonogenic assays as well as western blots were performed on human primary and murine engineered NTRK fusion-positive TRK WT and mutant cell models. Finally, zurletrectinib was tested in vivo in human xenografts and murine orthotopic glioma models harboring TRK-resistant mutations. Results: In vitro kinase and in cell-based assays showed that zurletrectinib, while displaying similar potency against TRKA, TRKB, and TRKC WT kinases, was more active than other FDA approved or clinically tested 1st- (larotrectinib) and next-generation (selitrectinib and repotrectinib) TRK inhibitors against most TRK inhibitor resistance mutations (13 out of 18). Similarly, zurletrectinib inhibited tumor growth in vivo in sub-cute xenograft models derived from NTRK fusion-positive cells at a dose 30 times lower when compared to selitrectinib. Computational modeling suggests this stronger activity to be the consequence of augmented binding affinity of zurletrectinib for TRK kinases. When compared to selitrectinib and repotrectinib, zurletrectinib showed increased brain penetration in rats 0.5 and 2 h following a single oral administration. Consistently, zurletrectinib significantly improved the survival of mice harboring orthotopic NTRK fusion-positive, TRK-mutant gliomas (median survival = 41.5, 66.5, and 104 days for selitrectinib, repotrectinib, and zurletrectinib respectively; P < 0.05). Conclusion: Our data identifies zurletrectinib as a novel, highly potent next-generation TRK inhibitor with stronger in vivo brain penetration and intracranial activity than other next-generation agents. © The Author(s) 2024. |
| Keywords: | controlled study; human cell; genetics; mutation; drug penetration; nonhuman; brain tumor; glioma; brain neoplasms; colorectal cancer; mouse; animal; animals; mice; gene; protein kinase inhibitor; animal experiment; animal model; in vitro study; tumor xenograft; drug effect; drug resistance; drug screening; pathology; drug resistance, neoplasm; xenograft model antitumor assays; cell line, tumor; pyrimidines; wild type; protein kinase inhibitors; membrane glycoproteins; pyrazole derivative; pyrazoles; membrane protein; tumor cell line; rat; gene fusion; oncogene proteins, fusion; rats; drug therapy; pyrimidine derivative; computer model; brain derived neurotrophic factor receptor; receptor, trkb; protein tyrosine kinase a; neurotrophin 3 receptor; receptor, trka; humans; human; male; female; article; tropomyosin-related kinase-b, human; receptor, trkc; larotrectinib; selitrectinib; ntrk gene; repotrectinib; oncogene fusion protein; ntrk1 protein, human; zurletrectinib; ntrk3 protein, human |
| Journal Title: | British Journal of Cancer |
| Volume: | 131 |
| Issue: | 3 |
| ISSN: | 0007-0920 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-08-24 |
| Start Page: | 601 |
| End Page: | 610 |
| Language: | English |
| DOI: | 10.1038/s41416-024-02760-1 |
| PUBMED: | 38902532 |
| PROVIDER: | scopus |
| PMCID: | PMC11300601 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA009748) acknowledged in PubMed and PDF -- Source: Scopus |
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