A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Recurrent cancer-associated ERBB4 mutations are transforming and confer resistance to targeted therapies
Tekijät: Ojala, Veera K.; Ahonen, Sini; Peltola, Sara; Tuohisto-kokko, Aura; Esparta, Olaya; Suominen, Peppi; Jokilammi, Anne; Farahani, Iman; Chakroborty, Deepankar; Dibus, Nikol; Boettcher, Steffen; Airenne, Tomi T.; Johnson, Mark S.; Eli, Lisa D.; Elenius, Klaus; Kurppa, Kari J.
Kustantaja: Wiley
Julkaisuvuosi: 2025
Lehti: Molecular Oncology
Artikkelin numero: 1878-0261.70189
ISSN: 1574-7891
eISSN: 1878-0261
DOI: https://doi.org/10.1002/1878-0261.70189
Julkaisun avoimuus kirjaamishetkellä: Avoimesti saatavilla
Julkaisukanavan avoimuus : Kokonaan avoin julkaisukanava
Verkko-osoite: https://doi.org/10.1002/1878-0261.70189
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/508251492
Receptor tyrosine kinase ERBB4 (HER4) is frequently mutated in human cancer, and ERBB4 mutations have been identified in patients relapsing on targeted therapy. Here, we addressed the functional consequences of recurrent cancer-associated ERBB4 mutations that are located at regions important for receptor activation and/or are paralogous to known oncogenic hotspot mutations in other ERBB genes. Eleven out of 18 analyzed mutations were transforming in cell models, thus suggesting oncogenic potential for more than half of the recurrent ERBB4 mutations. More detailed analyses of the most potent mutations, S303F, E452K, and L798R, showed that they are activating, can co-operate with other ERBB receptors and are sensitive to clinically available second-generation pan-ERBB inhibitors neratinib, afatinib, and dacomitinib. Furthermore, the S303F mutation, together with a previously identified activating ERBB4 mutation, E715K, promoted resistance to third-generation EGFR inhibitor osimertinib in EGFR-mutant lung cancer model in vitro and in vivo. Together, these results are expected to facilitate clinical interpretation of the most recurrent cancer-associated ERBB4 mutations. The findings provide rationale for testing the efficacy of clinically used pan-ERBB inhibitors in patients harboring driver ERBB4 mutations both in the treatment-naïve setting, and upon development of resistance to targeted agents.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
Julkaisussa olevat rahoitustiedot:
We thank Maria Tuominen and Mika Savisalo for skillful technical assistance, the bioinformatics (Jukka V. Lehtonen), drug discovery, and chemical biology and structural biology (FINStruct) infrastructure support from Biocenter Finland and CSC IT Center for Science for computational infrastructure support at the Structural Bioinformatics Laboratory, Abo Akademi University, the NordForsk Nordic POP (Patient-Oriented Products), NordicPharmaTrain projects, and the Solutions for Health strategic area of Abo Akademi University. The animal study was carried out with the support of Turku Center for Disease Modeling (TCDM), University of Turku, Finland; a member of Biocenter Finland. The authors would like to acknowledge the American Association for Cancer Research and its financial and material support in the development of the AACR Project GENIE registry, as well as members of the consortium for their commitment to data sharing. Interpretations are the responsibility of study authors. This study was supported by a research agreement with Puma Biotechnology (KE, KJK), as well as funding from the Research Council of Finland under grant numbers 346656 (KJK), 338466 (KJK), 316796 (KE), Sigrid Juselius Foundation (KJK, KE, TTA, MSJ), Jane and Aatos Erkko Foundation (KJK), Finnish Cultural Foundation (KJK, VKO), Cancer Foundation Finland (KE), Turku University Hospital (KE), InFLAMES Flagship Programme of the Research Council of Finland (decision number: 337531) (TTA, MSJ), the European Union-NextGenerationEU instrument and by the Research Council of Finland under grant number 352823 (TTA, MSJ), Cancer Society of South-West Finland (VKO), Instrumentarium Science Foundation (VKO), K. Albin Johansson Foundation (VKO), Orion Research Foundation (VKO), University of Turku Graduate School (VKO), and iCANDOC (The Finnish National Doctoral Education Pilot in Precision Cancer Medicine) at University of Turku (SP). Open access publishing facilitated by Turun yliopisto, as part of the Wiley-FinELib agreement.
