Article
Pharmacology & Pharmacy
Yue Zeng, Yuanqing Feng, Guihua Fu, Junlan Jiang, Xiaohan Liu, Yue Pan, Chunhong Hu, Xianling Liu, Fang Wu
Summary: The acquired resistance of EGFR-TKIs is inevitable and heterogeneous. Osimertinib is the standard second-line therapy for T790M-positive patients, but its efficacy in patients with concurrent multiple driver gene resistance is unclear. The T790M accompanying other driver gene resistance will be a new subtype, requiring new treatment options.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Oncology
Kana Watanabe, Ryota Saito, Eisaku Miyauchi, Hiromi Nagashima, Atsushi Nakamura, Shunichi Sugawara, Nobuyuki Tanaka, Hiroshi Terasaki, Tatsuro Fukuhara, Makoto Maemondo
Summary: The sensitive PNA-LNA clamp method can highly detect EGFR gene mutations in plasma. Plasma clearance of the activating gene mutation and the T790M mutation was observed in more than 70% of patients treated with osimertinib, and its clearance was correlated with the efficacy of osimertinib treatment. The C797S mutation, an osimertinib resistance mutation, was detected in only 8.1% of osimertinib-resistant cases.
Article
Chemistry, Medicinal
Tong-Hong Wang, Yann-Lii Leu, Chin-Chuan Chen, Hsin-Jung Li, Shuenn-Chen Yang, Kuo-Yen Huang, Chi-Yuan Chen
Summary: Psorachromene, a compound extracted from Psoralea corylifolia Linn. seeds, displays selective cytotoxic effects on NSCLC cells harboring activating EGFR mutations and inhibits activated EGFR signaling and kinase activity.
PHYTOTHERAPY RESEARCH
(2022)
Article
Oncology
Shang-Gin Wu, Chien-Hung Gow, Yi-Ling Chen, Yi-Nan Liu, Meng-Feng Tsai, Jin-Yuan Shih
Summary: This study investigated the efficacy of EGFR-tyrosine kinase inhibitors (TKIs) and the acquisition of T790M mutation in different subtypes of EGFR exon 19 deletion (Del-19) in advanced non-small-cell lung cancer (NSCLC). The results showed no significant differences in response rates between different Del-19 subtypes, but patients with indel E746 had longer progression-free survival (PFS) and overall survival (OS), while those with non-LRE deletions had the shortest survival. There were also no significant differences in the rates of T790M acquisition and the effectiveness of third-generation EGFR-TKIs in different Del-19 subgroups.
INTERNATIONAL JOURNAL OF CANCER
(2023)
Article
Oncology
Khi Pin Chua, Yvonne H. F. Teng, Aaron C. Tan, Angela Takano, Jacob J. S. Alvarez, Rahul Nahar, Neha Rohatgi, Gillianne G. Y. Lai, Zaw Win Aung, Joe P. S. Yeong, Kiat Hon Lim, Marjan Mojtabavi Naeini, Irfahan Kassam, Amit Jain, Wan Ling Tan, Apoorva Gogna, Chow Wei Too, Ravindran Kanesvaran, Quan Sing Ng, Mei Kim Ang, Tanujaa Rajasekaran, Devanand Anantham, Ghee Chee Phua, Bien Soo Tan, Yin Yeng Lee, Lanying Wang, Audrey S. M. Teo, Alexis Jiaying Khng, Ming Jie Lim, Lisda Suteja, Chee Keong Toh, Wan-Teck Lim, N. Gopalakrishna Iyer, Wai Leong Tam, Eng-Huat Tan, Weiwei Zhai, Axel M. Hillmer, Anders J. Skanderup, Daniel S. W. Tan
Summary: The study revealed the genetic and immune factors contributing to divergent TKI resistance and outcomes in EGFR-mutated NSCLC, showing the potential for tailored therapeutic approaches based on genomic and transcriptomic profiling. The research highlighted the importance of considering immune infiltration, genetic alterations, and cell lineage plasticity in predicting and overcoming drug resistance in lung cancer patients.
CLINICAL CANCER RESEARCH
(2021)
Article
Oncology
Sanjay Popat, Hyun Ae Jung, Shin Yup Lee, Maximilian J. Hochmair, Seung Hyeun Lee, Carles Escriu, Min Ki Lee, Maria R. Migliorino, Yong Chul Lee, Nicolas Girard, Hasan Daoud, Angela Marten, Satoru Miura
Summary: Sequential treatment with afatinib and osimertinib showed encouraging activity in patients with EGFR mutation-positive NSCLC and acquired T790M. Activity was observed across all subgroups, including patients with poor ECOG PS or brain metastases. ECOG PS and incidence of brain metastases remained stable prior to, and after, afatinib treatment.
Article
Chemistry, Medicinal
Lixue Chen, Yunhao Zhang, Liangliang Tian, Changyuan Wang, Tuo Deng, Xu Zheng, Tong Wang, Zhen Li, Zeyao Tang, Qiang Meng, Huijun Sun, Lei Li, Xiaodong Ma, Youjun Xu
Summary: A series of diphenylpyrimidine derivatives were designed and synthesized as noncovalent EGFR(T790M/L858R) inhibitors to improve biological activity and selectivity. Among them, compound 9d showed promising results in interfering with EGFR(T790M/L858R) binding with ATP and suppressing proliferation of H1975 cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Motohiro Tamiya, Akihiro Tamiya, Norio Okamoto, Yoshihiko Taniguchi, Kazumi Nishino, Shinji Atagi, Tomonori Hirashima, Fumio Imamura, Toru Kumagai, Hidekazu Suzuki
Summary: In this study, it was found that treating T790M-positive NSCLC patients with afatinib followed by osimertinib may lead to better outcomes. The T790M ratio was significantly correlated with osimertinib response, and there was no significant difference in T790M ratio between the Afa group and 1st-G group.
SCIENTIFIC REPORTS
(2021)
Article
Oncology
Dong-Wan Kim, Sang-We Kim, D. Ross Camidge, Catherine A. Shu, Kristen A. Marrone, Xiuning Le, Collin M. Blakely, Keunchil Park, Gee-Chen Chang, Sandip Pravin Patel, Gozde Kar, Zachary A. Cooper, Ramin Samadani, Michael Pluta, Rakesh Kumar, Suresh Ramalingam
Summary: This study evaluated the combination of the anti-CD73 antibody oleclumab with the third-generation EGFR TKI osimertinib in previously treated patients with advanced EGFR-mutated NSCLC. The treatment showed moderate activity and acceptable tolerability in this patient population.
JOURNAL OF THORACIC ONCOLOGY
(2023)
Review
Pharmacology & Pharmacy
Wen-Jing Liu, Lin Wang, Feng-Mei Zhou, Shu-Wen Liu, Wei Wang, Er-Jiang Zhao, Quan-Jun Yao, Wei Li, Yan-Qiu Zhao, Zhi Shi, Jian-Ge Qiu, Bing-Hua Jiang
Summary: In this study, it was found that elevated NOX4 expression was associated with acquired resistance to EGFR-TKIs. Knockdown of NOX4 increased sensitivity to gefitinib and osimertinib, while forced expression of NOX4 induced resistance. YY1 and IL-8 were identified as downstream targets of NOX4, regulating PD-L1 expression and TKIs resistance. These molecules may serve as potential biomarkers and therapeutic targets for overcoming TKIs resistance.
DRUG RESISTANCE UPDATES
(2023)
Article
Multidisciplinary Sciences
Tereza Vaclova, Ursula Grazini, Lewis Ward, Daniel O'Neill, Aleksandra Markovets, Xiangning Huang, Juliann Chmielecki, Ryan Hartmaier, Kenneth S. Thress, Paul D. Smith, J. Carl Barrett, Julian Downward, Elza C. de Bruin
Summary: T790M subclonality is associated with poorer response to osimertinib and shorter progression-free survival, likely due to co-occurring PIK3CA alterations which can be targeted by PI3K pathway inhibitors.
NATURE COMMUNICATIONS
(2021)
Article
Cell Biology
Zehe Ge, Miao Xu, Yuqian Ge, Guang Huang, Dongyin Chen, Xiuquan Ye, Yibei Xiao, Hongyu Zhu, Rong Yin, Hua Shen, Gaoxiang Ma, Lianwen Qi, Guining Wei, Dongmei Li, Shaofeng Wei, Meng Zhu, Hongxia Ma, Zhumei Shi, Xiuxing Wang, Xin Ge, Xu Qian
Summary: In this study, the researchers discovered that quercetin can directly bind with G6PD and inhibit its enzymatic activity, leading to a reduction in intracellular NADPH levels. This reduction inhibits M790 oxidation of EGFRT790M and induces the degradation of EGFRT790M, thus delaying the emergence of EGFRT790M mutation. Additionally, the researchers found that high levels of G6PD expression are associated with poor prognosis and the timing of EGFRT790M mutation in NSCLC patients.
Article
Biochemistry & Molecular Biology
Rui Yan, Xuying Huang, Heshu Liu, Zeru Xiao, Jian Liu, Guangyu An, Yang Ge
Summary: For lung adenocarcinoma with EGFR-sensitive mutations, EGFR-TKI is the first-line treatment, but acquired resistance remains a problem. Reversing acquired resistance through targeting key molecules driving EMT provides an alternative for patients. This study explores the role of DCLK1 as an EMT driver gene in acquired resistance of lung adenocarcinoma to EGFR-TKIs.
Article
Oncology
Byoung Chul Cho, Ji-Youn Han, Sang-We Kim, Ki Hyeong Lee, Eun Kyung Cho, Yun-Gyoo Lee, Dong-Wan Kim, Joo-Hang Kim, Gyeong-Won Lee, Jong-Seok Lee, Byoung Yong Shim, Jin-Soo Kim, Sang Hoon Chun, Sung Sook Lee, Hye Ryun Kim, Min Hee Hong, Jin Seok Ahn, Jong-Mu Sun, Youngjoo Lee, Dae Ho Lee, Ji Ah Kang, NaMi Lee, Mi-Jung Kwon, Carin Espenschied, Arielle Yablonovitch, Myung-Ju Ahn
Summary: This study evaluated the efficacy and safety of lazertinib in patients with advanced T790M-positive NSCLC after previous EGFR TKI therapy. The results demonstrated that lazertinib has a manageable safety profile with durable antitumor efficacy in this patient population.
JOURNAL OF THORACIC ONCOLOGY
(2022)
Article
Oncology
Li Ma, Haoyang Li, Dongpo Wang, Ying Hu, Mengjun Yu, Quan Zhang, Na Qin, Xinyong Zhang, Xi Li, Hui Zhang, Yuhua Wu, Jialin Lv, Xinjie Yang, Ruoying Yu, Shucai Zhang, Jinghui Wang
Summary: Dynamic cfDNA analysis using NGS can predict efficacy and resistance mechanisms of third-generation EGFR TKIs in NSCLC patients. Clearance of cfDNA and T790M level are significantly associated with clinical outcomes. The most common resistant mutation of third-generation TKIs is EGFR C797S.
FRONTIERS IN ONCOLOGY
(2021)