Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma
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Abstract
Abstract Purpose: Although clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non–small cell lung cancer (NSCLC), the factors that predict which subtype patients will be responsive to checkpoint blockade are not fully understood. Experimental Design: We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic, and clinical data from cohorts of lung adenocarcinoma public (discovery set) and internal (validation set) database and immunotherapeutic patients. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups. Results: We observed that TP53 mutation significantly increased expression of immune checkpoints and activated T-effector and interferon-γ signature. More importantly, the TP53/KRAS comutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of PD-L1+/CD8A+. Meanwhile, TP53- or KRAS-mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high (TH) cohort. Further analysis focused on the potential molecular mechanism revealed that TP53 or KRAS mutation altered a group of genes involved in cell-cycle regulating, DNA replication and damage repair. Finally, immunotherapeutic analysis from public clinical trial and prospective observation in our center were further confirmed that TP53 or KRAS mutation patients, especially those with co-occurring TP53/KRAS mutations, showed remarkable clinical benefit to PD-1 inhibitors. Conclusions: This work provides evidence that TP53 and KRAS mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding anti–PD-1/PD-L1 immunotherapy. Clin Cancer Res; 23(12); 3012–24. ©2016 AACR.
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Co-mutations of KRAS and TP53 are correlated with expression of PD-L1 in NSCLC.
“Further therapeutic considerations might arise from the finding that co-mutations of KRAS and tumor protein p53 gene (TP53) are correlated with expression of programmed death ligand 1 in NSCLC, 27,28 suggesting that these tumors might be predictive for antiprogrammed death 1/programmed death ligand 1 immunotherapy.”
From K-ras Mutation Subtypes in NSCLC and Associated Co-occuring Mutations in Other Oncogenic Pathways (2019) · cites this paper as [28]
Several preclinical studies suggested that tumors harboring KRAS mutations might be associated with a vulnerability to immunotherapies, in particular those with concomitant TP53 mutations.
“Interestingly, several preclinical studies suggested that tumors harboring KRAS mutations might be associated with a vulnerability to immunotherapies, in particular those with concomitant TP53 mutations (29, 92, 93).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [92]
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- Authors
- Dong, Z.-Y., Zhong, W.-Z., Zhang, X.-C., Su, J., Xie, Z., Liu, S.-Y., Tu, H.-Y., Chen, H.-J., Sun, Y.-L., Zhou, Q., Yang, J.-J., Yang, X.-N., Lin, J.-X., Yan, H.-H., Zhai, H.-R., Yan, L.-X., Liao, R.-Q., Wu, S.-P., & Wu, Y.-L.
- Affiliations
- Guangdong General Hospital (CN)
- 1Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2017-06-14
- Volume
- 23
- Issue
- 12
- Pages
- 3012-3024
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2561459036
- Cited by
- 959
- References
- 50
- Citations by year
- 2026: 51 · 2025: 67 · 2024: 104 · 2023: 125 · 2022: 166 · 2021: 179 · 2020: 136 · 2019: 55 · 2018: 55 · 2017: 21
- FWCI
- 23.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Guangzhou Science and Technology Bureau (2014Y2-00050 and 2014Y2-00545)
- The National Key Research and Development Program of China (2016YFC1303800)
- National Natural Science Foundation (81372285)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- TP53 mutation, KRAS mutation, lung adenocarcinoma, non-small cell lung cancer, anti-PD-1 therapy, PD-L1 expression, immunotherapy response prediction, CD8A, interferon-gamma signature, tumor mutational burden, transversion mutations, DNA repair, cell cycle genes
- MeSH terms
- Adenocarcinoma of Lung, Adenocarcinoma, Female, Humans, Immunotherapy, Lung Neoplasms, Male, Mutation, Prognosis, Biomarkers, Tumor, Tumor Suppressor Protein p53, Proto-Oncogene Proteins p21(ras), Proteomics, B7-H1 Antigen, Programmed Cell Death 1 Receptor
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