The DOI matches its Crossref record; 62 of the 62 references it cites were found in a registry or an index.
Genetic Aberrations in the CDK4 Pathway Are Associated with Innate Resistance to PD-1 Blockade in Chinese Patients with Non-Cutaneous Melanoma
Open accessPublished version of a preprint
Abstract
Purpose: PD-1 checkpoint blockade immunotherapy induces long and durable response in patients with advanced melanoma. However, only a subset of patients with melanoma benefit from this approach. The mechanism triggering the innate resistance of anti–PD-1 therapy remains unclear. Experimental Design: Whole-exome sequencing (WES) and RNA sequencing (RNA-Seq) analyses were performed in a training cohort (n = 31) using baseline tumor biopsies of patients with advanced melanoma treated with the anti–PD-1 antibody. Copy-number variations (CNVs) for the genes CDK4, CCND1, and CDKN2A were assayed using a TaqMan copy-number assay in a validation cohort (n = 85). The effect of CDK4/6 inhibitors combined with anti–PD-1 antibody monotherapy was evaluated in PD-1–humanized mouse (C57BL/6-hPD-1) and humanized immune system (HIS) patient-derived xenograft (PDX) models. Results: WES revealed several significant gene copy-number gains in the patients of no clinical benefit cohort, such as 12q14.1 loci, which harbor CDK4. The association between CDK4 gain and innate resistance to anti–PD-1 therapy was validated in 85 patients with melanoma (P < 0.05). RNA-Seq analysis of CDK4-normal cell lines and CDK4-normal tumors showed altered transcriptional output in TNFα signaling via NF-κB, inflammatory response, and IFNγ response gene set. In addition, CDK4/6 inhibitor (palbociclib) treatment increased PD-L1 protein levels and enhanced efficacy (P < 0.05) in the C57BL/6-hPD-1 melanoma cell and the HIS PDX model. Conclusions: In summary, we discovered that genetic aberrations in the CDK4 pathway are associated with innate resistance to anti–PD-1 therapy in patients with advanced melanoma. Moreover, our study provides a strong rationale for combining CDK4/6 inhibitors with anti–PD-1 antibody for the treatment of advanced melanomas.
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“CDK4/6 inhibitors improved the efficacy of α-PD-1 in murine models by enhancing lymphocyte infiltration and TIL activities [245–248].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [246]
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IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade
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Combination strategies with PD-1/PD-L1 blockade: current advances and future directions
Yi, M., Zheng, X., Niu, M., Zhu, S., Ge, H., & Wu, K. (2022) · Molecular Cancer · doi:10.1186/s12943-021-01489-2 · Cited by 1,445
Basurto‐Lozada, P., Molina‐Aguilar, C., Castaneda‐Garcia, C., Vázquez‐Cruz, M. E., Garcia‐Salinas, O. I., Álvarez‐Cano, A., Martínez‐Said, H., Roldán‐Marín, R., Adams, D. J., Possik, P. A., et al. (2021) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12885 · Cited by 154
Metadata
- Authors
- Yu, J., Yan, J., Guo, Q., Chi, Z., Tang, B., Zheng, B., Yu, J., Yin, T., Cheng, Z., Wu, X., Yu, H., Dai, J., Sheng, X., Si, L., Cui, C., Bai, X., Mao, L., Lian, B., Wang, X., Yan, X., Li, S., Zhou, L., Flaherty, K. T., Guo, J., & Kong, Y.
- Affiliations
- Peking University Cancer Hospital (CN)
- Harvard University (US)
- 1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2019-11-01
- Volume
- 25
- Issue
- 21
- Pages
- 6511-6523
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2965059444
- Cited by
- 100
- References
- 62
- Citations by year
- 2026: 3 · 2025: 13 · 2024: 16 · 2023: 20 · 2022: 21 · 2021: 16 · 2020: 8 · 2019: 3
- FWCI
- 5.11
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Greater South Information System
- Funders
- Natural Science Foundation of China (81672696, 81772912)
- Health Science Center (DFL20181101)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Keywords
- anti-PD-1 resistance, copy number gain, CDK4, CDK4/6 inhibitors, palbociclib, PD-L1 expression, TNF signaling, NF-κB, combination immunotherapy, patient-derived xenografts, Chinese patients
- MeSH terms
- Exome Sequencing, Animals, Humans, Interferon-gamma, Melanoma, Piperazines, Pyridines, Tumor Necrosis Factor-alpha, Signal Transduction, Drug Resistance, Neoplasm, Cyclin D1, Cyclin-Dependent Kinase Inhibitor p16, Protein Kinase Inhibitors, Cyclin-Dependent Kinase 4, Mice, Cell Cycle Checkpoints, B7-H1 Antigen, Programmed Cell Death 1 Receptor, Heterografts
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