Association of Tumor Protein p53 and Ataxia-Telangiectasia Mutated Comutation With Response to Immune Checkpoint Inhibitors and Mortality in Patients With Non–Small Cell Lung Cancer

Chen, Yu; Chen, Gang; Li, Jin; Huang, Yingying; Li, Yi; Lin, Jing; Chen, Lizhu; Lu, Jianping; Wang, Yuqi; Wang, Changxi; Pan, Leong Kin; Xia, Xuefeng; Yi, Xin; Chen, Chuanben; Zheng, Xiongwei; Guo, Zengqing; Pan, Jianji

doi:10.1001/jamanetworkopen.2019.11895

Cited by 58 publications

(50 citation statements)

References 46 publications

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“…TMB has emerged as a predictive biomarker in immunotherapy response across many tumor types including HNSCC [9] . NGS studies have shown a clear association between TP53 mutated tumors with high TMB levels and robust clinical benefit from ICIs in NSCLC [ 47 , 48 ]. In this direction, we evaluated the association between TP53 mutation status, TMB score and overall survival in primary and metastatic (lung and liver) HNSCC tumors of patients treated with ICIs.…”

Section: Discussionmentioning

confidence: 99%

TP53 mutational landscape of metastatic head and neck cancer reveals patterns of mutation selection

Klinakis

Ράμπιας

2020

EBioMedicine

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Background Head and neck squamous cell carcinoma is a heterogeneous disease with respect to the anatomic site of the primary tumor. On the other hand, it is highly recurrent, and once metastatic, it is associated with poor prognosis. TP53 is the most commonly mutated gene in primary disease. TP53 mutations occur in different structural elements of the protein while the biological outcome can be diverse. Methods Here we aimed to find differences in the mutation profile of TP53 in primary and metastatic disease and the impact of TP53 mutations in metastasis, specific copy number alterations, tumor mutation burden and response to immune checkpoint inhibitors. Somatic mutation and clinical data for 512 primary and 134 metastatic biopsies were studied. Findings Overall TP53 mutation frequency is significantly lower in metastases compared to primary tumors. One the other hand, missense mutations in the DNA binding region are significantly enriched in metastases and are associated with a common fragile site in chromosome 11, leading to amplification and overexpression of genes with established role in metastasis. Finally, TP53 mutations are associated with higher TMB score in metastatic but not primary tumors, and poorer response to immune checkpoint inhibitors for the latter. Interpretation TP53 mutations affect clinical and molecular aspects of head and neck tumorigenesis including metastasis, genetic alterations and therapeutic response. Funding This work was supported by a Horizon 2020 grant (801347) to AK, and a Greek General Secretariat for Research and Technology and the Hellenic Foundation for Research and Innovation grant (472‐EpiNotch) to TR.

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Section: Discussionmentioning

confidence: 99%

TP53 mutational landscape of metastatic head and neck cancer reveals patterns of mutation selection

Klinakis

Ράμπιας

2020

EBioMedicine

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“…Therefore, the effect of p53 status on PARP inhibitor sensitivity requires further clarification. Although co-mutation of both ATM and TP53 is rare [59], co-mutation has been shown to occur in 2-3% of non-small cell lung cancer where it increases tumour mutation burden and correlates with better response to immune checkpoint therapy [60], suggesting additional opportunities for targeted therapy for ATM-deficient tumours.…”

Section: Targeting Atm-deficient Cancersmentioning

confidence: 99%

ATM-Deficient Cancers Provide New Opportunities for Precision Oncology

Jette

Kumar

Radhamani

et al. 2020

Cancers

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Poly-ADP ribose polymerase (PARP) inhibitors are currently used in the treatment of several cancers carrying mutations in the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2, with many more potential applications under study and in clinical trials. Here, we discuss the potential for extending PARP inhibitor therapies to tumours with deficiencies in the DNA damage-activated protein kinase, Ataxia-Telangiectasia Mutated (ATM). We highlight our recent findings that PARP inhibition alone is cytostatic but not cytotoxic in ATM-deficient cancer cells and that the combination of a PARP inhibitor with an ATR (ATM, Rad3-related) inhibitor is required to induce cell death.

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“…P53, mutated in PLC, is a pivotal tumor suppressor gene and a signi cant mainstay in our body's natural anti-cancer defense [66]. Several studies have shown that P53 in liver cancer can function to restrain tumor development [67,68].…”

Section: Discussionmentioning

confidence: 99%

Data Mining and System Pharmacology to Elucidate the Efficiency and Mechanism of Chinese Medicine in Treating Primary Liver Cancer

Zhang

Zeng

Gao

et al. 2020

Preprint

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BACKGROUNDPiling studies have demonstrated that Chinese medicine (CM) is effective in treating PLC. However, underlying mechanism of CM in treating PLC remains confused. MATERIAL AND METHODThe information of 524 patients with PLC were collected and separated to CM group and Less-CM group based on the time of taking CM. Then, the prescriptions in CM group were collected to identify the corn drugs. System Pharmacology was employed to explore the mechanism of corn drugs in treating PLC.RESULTSIn univariate and multivariate analysis, taking Chinese medicines more than 6 months was an independent prognostic factor. Then, Traditional Chinese Medicine Inheritance Support System was employed to find out the core drugs that really benefit for PLC patients. Totally, 153 ingredients from 9 core drugs (HXCF) were screened out. Fifty-five genes were identified for HXCF against PLC. The pathways were found as the mechanism of HXCF to treat PLC. Docking studies suggested amount of ingredients in HXCF exerts therapeutic effects against PLC, at least in part, by modulating the function of c-JUN and IL-6.CONCLUSIONOur results verified the effectiveness of CM in treating PLC and mined the corn drugs. What’s more, our result also predicted active components and potential targets of HXCF for the application to PLC from a holistic perspective, as well as provided valuable direction for further research of HXCF and improved comprehension of PLC.

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Association of Tumor Protein p53 and Ataxia-Telangiectasia Mutated Comutation With Response to Immune Checkpoint Inhibitors and Mortality in Patients With Non–Small Cell Lung Cancer

Abstract: This cohort study examines the association of comutation of tumor protein p53 (TP53) and ataxia-telangiectasia mutated (ATM) genes with response to immune checkpoint inhibitor (ICI) treatment and overall survival among patients with non–small cell lung cancer (NSCLC).

Cited by 58 publications

References 46 publications

TP53 mutational landscape of metastatic head and neck cancer reveals patterns of mutation selection

TP53 mutational landscape of metastatic head and neck cancer reveals patterns of mutation selection

ATM-Deficient Cancers Provide New Opportunities for Precision Oncology

Data Mining and System Pharmacology to Elucidate the Efficiency and Mechanism of Chinese Medicine in Treating Primary Liver Cancer

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