HPK1 kinase inhibitor: a sufficient approach to target HPK1 to modulate T cell activation in cancer immunotherapy compared with degraders
Augmented T-cell receptor (TCR)-induced activation in HPK1-knockout Jurkat cells was inhibited by complementation of wildtype, but not kinase-dead HPK1. HPK1 K46E-knockin and K46*-knockin Jurkat cells showed comparable levels of enhanced TCR-induced activation compared with control HPK1-wildtype Jurkat cells. Similarly, HPK1 kinase inhibitor (Compound 1) and cereblon-based (CRBN-based) HPK1 degrader (Compound 2) elicited similar degrees of maximum TCR-induced activation in primary human peripheral blood T cells. In summary, the results of this study suggested that HPK1 kinase inhibitor may be sufficient for HPK1 targeting in T cell mediated cancer immunotherapy.
Authors
- Xiaopeng Cai (ORCID: https://orcid.org/0000-0002-8332-0151)
- Xinyi Zhu (ORCID: https://orcid.org/0000-0002-7361-8958)
- Lai Wang (ORCID: https://orcid.org/0000-0002-3323-7210)
- Sanjia Xu (ORCID: https://orcid.org/0000-0002-3411-5151)
- Haimei Xing
- Jing Li (ORCID: https://orcid.org/0000-0001-9268-4689)
- Ye Liu (ORCID: https://orcid.org/0000-0001-9156-9515)
- Qin Wang (ORCID: https://orcid.org/0000-0001-8821-8677)
- Zhiwei Wang (ORCID: https://orcid.org/0000-0001-5643-9344)
- Xuesong Liu (ORCID: https://orcid.org/0000-0001-6491-0677)
- Xingxing Wang (ORCID: https://orcid.org/0000-0002-8173-7148)
- Xinwen Zhang (ORCID: https://orcid.org/0000-0003-2500-4756)
- Ali Wang (ORCID: https://orcid.org/0000-0003-4993-005X)
- Xi Yuan
Institutions
- BeiGene (China) (CN)
Publication Details
- Journal
- Frontiers in Immunology
- Published
- 2025-02-06
- DOI
- https://doi.org/10.3389/fimmu.2025.1449106
- Citations
- 3
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 3.14
Funders
- BeiGene