ArticleMolecular therapy : the journal of the American Society of Gene Therapy2024
Tumor-intrinsic CDC42BPB confers resistance to anti-PD-1 immune checkpoint blockade in breast cancer.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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4 citing papers in PubMed.
- AURKB-mediated phosphorylation of metabolic enzyme CD73 drives immune suppression and renal cell carcinoma progression.Cell death and differentiation · 2026Article
- Implications of Rho GTPase signaling in cancer immunotherapy.Biochemical Society transactions · 2026Review
- A case of quadruple wild-type gastrointestinal stromal tumor with CDC42BPB::NTRK3 fusion and abundant lymphoid infiltration.Diagnostic pathology · 2025Article
- Tumor-intrinsic kinase: A promising target for overcoming resistance to immune checkpoint blockade therapies.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
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Abstract
Immune checkpoint blockade has been used to treat breast cancer, but the clinical responses remain relatively poor. We have used the CRISPR-Cas9 kinome knockout library consisting of 763 kinase genes to identify tumor-intrinsic kinases conferring resistance to anti-PD-1 immune checkpoint blockade. We have identified the CDC42BPB kinase as a potential target to overcome the resistance to anti-PD-1 immune checkpoint blockade immunotherapy. We found that CDC42BPB is highly expressed in breast cancer patients who are non-responsive to immunotherapy. Furthermore, a small-molecule pharmacological inhibitor, BDP5290, which targets CDC42BPB, synergized with anti-PD-1 and enhanced tumor cell killing by promoting T cell proliferation in both in vitro and in vivo assays. Moreover, anti-PD-1-resistant breast cancer cells showed higher expression of CDC42BPB, and its inhibition rendered the resistant cells more susceptible to T cell killing in the presence of anti-PD-1. We also found that CDC42BPB phosphorylated AURKA, which in turn upregulated PD-L1 through cMYC. Our results have revealed a robust link between tumor-intrinsic kinase and immunotherapy resistance and have provided a rationale for a unique combination therapy of CDC42BPB inhibition and anti-PD-1 immunotherapy for breast cancer.
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