Significance of TP53 Mutation in Cellular Process and Disease Progression in Lung Adenocarcinoma

Analysis of the TCGA data showed TP53 mutations in 22% of LUAD patients. Clinicopathological analyses demonstrated that TP53 mutation was correlated with the disease progression but not prognosis. We identified 1935 differentially expressed genes (DEGs). Functional enrichment analysis showed that the DEGs were mainly concentrated in metabolism, cell differentiation, and cancer-related pathways. The top hub genes were identified and disease analysis revealed the most critical genes related to disease progression and prognosis. The expression levels of several of these genes were then tested in tumor tissues. Our results showed that TP53 mutation plays a critical role in cellular process and the clinicopathological findings in LUAD. We also identified potential key genes, which could provide novel evidence for individualized treatment. READ ARTICLE

Genetic Testing and Molecular Biomarkers DOI:10.1089/gtmb.2020.0304

Authors: Yongbo Hou, Sheng Tan, Guoxiang Wang

Real-World OutcomesKirk SmithMay 1, 2021TP53, adenocarcinoma, lung

Decoding the Evolutionary Response to Ensartinib in Patients With ALK-Positive NSCLC by Dynamic Circulating Tumor DNA Sequencing

By implementing dynamic circulating tumor DNA (ctDNA) analysis, we explored the impact of TP53 mutations on tumor evolution and resistance mechanisms to ensartinib in patients with ALK-positive NSCLC. Our study highlighted the advantage of ctDNA analysis for monitoring tumor evolution. TP53 mutations promoted genetic evolution and accelerated occurrence of resistance. We also unveiled ALK-dependent resistance mechanisms, mainly by G1269A, G1202R, and E1210K mutations, and ALK-independent resistance mechanisms to ensartinib. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.01.1615

Authors: Yunpeng Yang, Jie Huang, Tao Wang, Jianya Zhou, Jing Zheng, Jifeng Feng, Wu Zhuang, Jianhua Chen, Jun Zhao, Wei Zhong, Yanqiu Zhao, Yiping Zhang, Yong Song, Yi Hu, Zhuang Yu, Youling Gong, Yuan Chen, Feng Ye, Shucai Zhang, Lejie Cao, Yun Fan, Gang Wu, Yubiao Guo, Chengzhi Zhou, Kewei Ma, Jian Fang, Weineng Feng, Yunpeng Liu, Zhendong Zheng, Gaofeng Li, Huijie Wang, Shundong Cang, Ning Wu, Wei Song, Xiaoqing Liu, Shijun Zhao, Lieming Ding, Li Mao, Giovanni Selvaggi, Larry Zhu, Shanshan Xiao, Xiaobin Yuan, Zhilin Shen, Li Zhang

Pre-ClinicalKirk SmithMay 1, 2021ALK+, NSCLC, ctDNA, TP53, Resistance mechanism

Targeting a neoantigen derived from a common TP53 mutation

Like our ALK vaccine, this group had worked on a TP53 vaccine, using a similar technique Dr. Chairle described for ALK. TP53 (tumor protein p53) is the most commonly mutated cancer driver gene, but drugs that target mutant tumor suppressor genes, such as TP53, are not yet available. Here, we describe the identification of an antibody highly specific to the most common TP53 mutation (R175H, in which arginine at position 175 is replaced with histidine) in complex with a common human leukocyte antigen–A (HLA-A) allele on the cell surface. We describe the structural basis of this specificity and its conversion into an immunotherapeutic agent: a bispecific single-chain diabody. Despite the extremely low p53 peptide-HLA complex density on the cancer cell surface, the bispecific antibody effectively activated T cells to lyse cancer cells that presented the neoantigen in vitro and in mice. This approach could in theory be used to target cancers containing mutations that are difficult to target..... READ ARTICLE

Science DOI: 10.1126/science.abc8697

Authors: Emily Han-Chung Hsiue, Katharine M. Wright, Jacqueline Douglass, Michael S. Hwang, Brian J. Mog, Alexander H. Pearlman, Suman Paul, Sarah R. DiNapoli, Maximilian F. Konig, Qing Wang, Annika Schaefer, Michelle S. Miller, D. Skora, P. Aitana Azurmend, Michael B. Murphy, Liu, Evangeline Watson, Yana Li, M. Pardoll, Chetan Bettegowda, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein,Sandra B. Gabelli, Shibin Zhou

Pre-ClinicalKirk SmithMarch 1, 2021TP53, T cells

Lorlatinib in pretreated ALK- or ROS1-positive lung cancer and impact of TP53 co-mutations: results from the German early access program

Our data from real-life practice demonstrate the efficacy of lorlatinib in mostly heavily pretreated patients, providing a clinically meaningful option for patients with resistance mutations not covered by other targeted therapies and those with BM or leptomeningeal carcinomatosis. READ ARTICLE

Therapeutic advances in Medical Oncology DOI: 10.1177/1758835920980558

Authors: Nikolaj Frost, Petros Christopoulos, Diego Kauffmann-Guerrero, Jan Stratmann, Richard Riedel, Monica Schaefer, Jürgen Alt, Sylvia Gütz, Daniel C Christoph, Eckart Laack, Martin Faehling, Richard Fischer, Klaus Fenchel, Sebastian Haen, Lukas Heukamp, Christian Schulz and Frank Griesinger

Lorlatinib in pretreated ALK- or ROS1-positive lung cancer and impact of TP53 co-mutations: results from the German early access program

We report on the results of the German early access program (EAP) with the
third-generation ALK- and ROS1-inhibitor lorlatinib. Our data from real-life practice demonstrate the efficacy of lorlatinib in mostly heavily pretreated patients, providing a clinically meaningful option for patients with resistance mutations not covered by other targeted therapies and those with BM or leptomeningeal carcinomatosis. READ ARTICLE

Therapeutic advances in Medical Oncology DOI: 10.1177/1758835920980558

Authors: Nikolaj Frost, Petros Christopoulos, Diego Kauffmann-Guerrero, Jan Stratmann, Richard Riedel, Monica Schaefer, Jürgen Alt, Sylvia Gütz, Daniel C. Christoph, Eckart Laack, Martin Faehling, Richard Fischer, Klaus Fenchel, Sebastian Haen, Lukas Heukamp, Christian Schulz, Frank Griesinger

Real-World OutcomesKirk SmithFebruary 1, 2021ALK, brain metastases, early access program, NSCLC, ROS1, TP53, lorlatinib

Advance of theragnosis biomarkers in lung cancer: from clinical to molecular pathology and biology

One distinct molecular subtype of non-small cell lung cancer (NSCLC) is defined by rearrangement of the anaplastic lymphoma kinase (ALK). The increasing knowledge over the last years has enabled the continuous improvement of ALK inhibitors; however, resistance in these patients remains a major concern. In this review, we summarize recent findings in ALK+-adenocarcinoma of the lung, highlighting the role of TP53 mutations in this specific cancer type and suggest new diagnostic strategies for the future, in order to improve patient’s outcome. READ ARTICLE

Journal of Thoracic Disease
DOI:10.21037/jtd.2018.12.03

Authors: Christina Alidousty, Till Baar, Carina Heydt, Svenja Wagener-Ryczek, Anna Kron, Juergen Wolf, Reinhard Buettner, Anne Maria Schultheis

Concomitant resistance mechanisms to multiple tyrosine kinase inhibitors in ALK-positive non-small cell lung cancer

ALK tyrosine kinase inhibitors (TKIs), including crizotinib and several next generation TKIs, have demonstrated beneficial clinical outcomes in ALK-positive non-small cell lung cancer (NSCLC). However, resistance mechanisms following multiple TKI treatments in ALK-positive NSCLC are not fully elucidated.
Mutation profiles of 422 cancer-relevant genes in 52 patients with post-TKI biopsy samples were analyzed using next-generation sequencing (NGS), and compared between patients receiving crizotinib alone (n = 35) and multi-TKIs (n = 17).
Concurrent ALK activating mutations and/or upregulated bypass signaling are more enriched in patients undergoing multiple ALK TKI treatments compared to crizotinib alone. Concomitant TP53 mutation correlated to unfavorable survival when receiving a single TKI crizotinib. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2018.11.024

Authors: Yongfeng Yu, Qiuxiang Ou, Xue Wu, Hairong Bao,
Yan Ding, Yang W. Shao, Shun Lu