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EGFR inhibitor

Shuhang Wang, Yongping Song, Feifei Yan, Delong Liu
The tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) are becoming the first line of therapy for advanced non-small cell lung cancer (NSCLC). Acquired mutations in EGFR account for one of the major mechanisms of resistance to the TKIs. Three generations of EGFR TKIs have been used in clinical applications. AZD9291 (osimertinib; Tagrisso) is the first and only FDA approved third-generation EGFR TKI for T790M-positive advanced NSCLC patients. However, resistance to AZD9291 arises after 9-13 months of therapy...
October 21, 2016: Frontiers of Medicine
Ju Hui Jeong, Yong Jin Oh, Taeg Kyu Kwon, Young Ho Seo
The molecular chaperone Hsp90 has emerged as an attractive cancer therapeutic target due to its role in cellular homeostasis by modulating the stabilization and maturation of many oncogenic proteins. In this study, we designed and synthesized a series of Hsp90 inhibitors that hybridized NVP-AUY992 (2) and PU3 (3) in the chalcone scaffold using a structure-based approach. Our results indicate that compound 1g inhibited the proliferation of gefitinib-resistant non-small cell lung cancer (H1975) cells, downregulated the expression of client proteins of Hsp90 including EGFR, MET, Her2 and Akt, and up-regulated the expression of Hsp70...
October 21, 2016: Archives of Pharmacal Research
Jing Zhao, Xin Ye, Yan Xu, Minjiang Chen, Wei Zhong, Yun Sun, Zhenfan Yang, Guanshan Zhu, Yi Gu, Mengzhao Wang
PURPOSE: Central nervous system (CNS) is the prevalent site for metastases in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-relapsed NSCLC patients. To understand the EGFR mutation status in paired cerebrospinal fluid (CSF) and plasma samples after EGFR-TKI treatment failure might be useful to guide the treatment of intra- and extracranial tumors in those patients. METHODS: Paired CSF and plasma samples were collected from seven NSCLC patients with CNS metastases after EGFR-TKI failure...
October 21, 2016: Cancer Chemotherapy and Pharmacology
(no author information available yet)
Findings from a phase I/II study indicate a higher response rate among patients with BRAF-mutant metastatic colorectal cancer treated with an EGFR inhibitor alongside dual, as opposed to single-level, MAPK blockade. Panitumumab combined with trametinib and dabrafenib only modestly increased median progression-free survival, however; a short-lived decrease in responders' BRAF V600E mutant allele fraction and the emergence of RAS mutations may have been contributing factors.
October 21, 2016: Cancer Discovery
Chao Ding, Shaopeng Chen, Cunlong Zhang, Guangnan Hu, Wei Zhang, Lulu Li, Yu Zong Chen, Chunyan Tan, Yuyang Jiang
By merging the critical pharmacophore of EGFR/HER2 and HDAC inhibitors into one compound, a novel series of EGFR, HER-2, and HDAC multitarget inhibitors were synthesized. Compounds 9a-l contained 4-anilinoquinazolines with C-6 triazole-linked long alkyl chains of hydroxamic acid and displayed excellent inhibition against these enzymes (compound 9d exhibited the best inhibitory potency on wild-type EGFR, HDAC1, and HDAC6 with IC50 values 0.12nM, 0.72nM and 3.2nM individually). Furthermore, compounds 9b and 9d potently inhibited proliferation of five human cancer cell lines (with IC50 values between 0...
October 10, 2016: Bioorganic & Medicinal Chemistry
Sanja Dacic, Liza C Villaruz, Shira Abberbock, Alyssa Mahaffey, Pimpin Incharoen, Marina N Nikiforova
Break-apart ALK FISH probe is the FDA approved approach for detection of ALK rearrangements in lung carcinoma patients who may benefit from ALK kinase inhibitors. The FISH assay can be technically challenging and difficult to interpret. ALK immunohistochemistry and next generation sequencing have been proposed as alternative approaches. In this study, we compared various ALK -FISH patterns to next -generation sequencing (NGS) for gene fusion detection, ALK immunohistochemistry (IHC) and tumor responses to crizotinib...
October 17, 2016: Oncotarget
Shuyang Yao, Xiuyi Zhi, Ruotian Wang, Kun Qian, Mu Hu, Yi Zhang
BACKGROUND: Epidermal growth factor receptor (EGFR) mutations occur in about 50% of Asian patients with non-small cell lung cancer (NSCLC). Patients with advanced NSCLC and EGFR mutations derive clinical benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs). This study assessed the efficacy and safety of adjuvant icotinib without chemotherapy in EGFR-mutated NSCLC patients undergoing resection of stage IB-IIIA. METHODS: Our retrospective study enrolled 20 patients treated with icotinib as adjuvant therapy...
September 2016: Thoracic Cancer
Aimi Huang, Rong Li, Jikai Zhao, Xiaofei Wang, Bo Jin, Yanjie Niu, Jie Zhang, Liyan Jiang, Baohui Han
This article demonstrates a case of a lung adenocarcinoma patient in stage IV harboring an epidermal growth factor receptor (EGFR) 19 exon deletion mutation treated with 500 mg/m(2) pemetrexed and 75 mg/m(2) cisplatin on day 1, sequenced with 250 mg gefitinib on prescription on days 4-28 for six cycles as first-line, then by gefitinib combined with pemetrexed as maintenance therapy. The patient achieved a partial response. Performance status increased from grade 2 to 1. The progression-free survival period was 17 months...
September 2016: Thoracic Cancer
Chee Khoon Lee, Johnathan Man, Sally Lord, Matthew Links, Val Gebski, Tony Mok, James Chih-Hsin Yang
INTRODUCTION: We performed a meta-analysis to assess the role of immune-checkpoint inhibitors as second-line therapy in epidermal growth factor receptor (EGFR) mutant advanced non-small cell lung cancer (NSCLC). METHODS: Randomized trials comparing immune-checkpoint inhibitors against chemotherapy were identified. We retrieved the hazard ratio (HR) and 95% confidence interval (CI) for overall survival (OS) of the intention-to-treat population and EGFR mutation defined subgroups...
October 17, 2016: Journal of Thoracic Oncology
Antonin Levy, Etienne Bardet, Benjamin Lacas, Jean-Pierre Pignon, Julien Adam, Ludovic Lacroix, Xavier Artignan, Pierre Verrelle, Cécile Le Péchoux
BACKGROUND: Gefitinib is an oral EGFR tyrosine kinase inhibitors which may act as a radiosensitizer. PATIENTS AND METHODS: This phase II study evaluated the efficacy of gefitinib 250 mg once daily in combination with thoracic radiotherapy (66 Gy in 6.5 weeks, 2 Gy/day, 5 fractions/week) followed by consolidation chemotherapy (IV cisplatin and vinorelbine) as first line treatment in a population of unselected stage IIIB NSCLC patients according to EGFR mutation status...
October 18, 2016: Oncotarget
Dariusz Wodziak, Aiwen Dong, Michael F Basin, Anson W Lowe
A recently published study identified Anterior Gradient 2 (AGR2) as a regulator of EGFR signaling by promoting receptor presentation from the endoplasmic reticulum to the cell surface. AGR2 also promotes tissue regeneration in amphibians and fish. Whether AGR2-induced EGFR signaling is essential for tissue regeneration in higher vertebrates was evaluated using a well-characterized murine model for pancreatitis. The impact of AGR2 expression and EGFR signaling on tissue regeneration was evaluated using the caerulein-induced pancreatitis mouse model...
2016: PloS One
Jun Li, Jie Ao, Kai Li, Jie Zhang, Yanyan Li, Le Zhang, Yuyan Wei, Di Gong, Junping Gao, Weiwei Tan, Lugang Huang, Lunxu Liu, Ping Lin, Yuquan Wei
Multidrug resistance (MDR) is one of the most important contributors to the high mortality of cancer and remains a major concern. We previously found that zinc finger protein 32 (ZNF32), an important transcription factor associated with cancer in Homo sapiens, protects tumor cells against cell death induced by oxidative stress and other stimuli. We thus hypothesized that ZNF32 might enable the tolerance of cancer cells to anti-tumor drugs because higher ZNF32 expression has been found in cancer tissues and in drug-resistant lung adenocarcinoma (AC) cells...
October 20, 2016: Cell Death & Disease
Yuko Ohta, Azusa Ishizuka, Hisatomi Arima, Shinichiro Hayashi, Yoshio Iwashima, Masatsugu Kishida, Fumiki Yoshihara, Satoko Nakamura, Yuhei Kawano
Uric acid (UA) has been associated with hypertension, renal disease and cardiovascular disease. The aim of the present study was to compare the UA-lowering effects of a standard dose of the UA synthesis inhibitor febuxostat to a standard dose of the uricosuric agent benzbromarone, and to investigate the effects of a low-dose combination of both agents in hypertensive patients with hyperuricemia. Twenty hypertensive patients with inadequate UA control were administered febuxostat 40 mg (Feb), benzbromarone 50 mg (Ben) and febuxostat 20 mg and benzbromarone 25 mg (feb/ben) for 3 months each in a randomized modified crossover manner...
October 20, 2016: Hypertension Research: Official Journal of the Japanese Society of Hypertension
Xiaoyan Kang, Nan Zhu, Xia Song
In recent years, targeted drugs occupy a pivotal position in the treatment of non-small cell lung cancer (NSCLC), drugs targeting epidermal growth factor receptor (EGFR) has been widely used in clinical practice, it is of milestone significance. V-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors targeted at BRAF gene have obviously clinical efficacy to specific advantages populations with little side-effect, and be well tolerated. It is discovered recently that drug resistance also exists in BRAF inhibitors like other targeted drugs, the mechanism of drug resistance is being studied...
October 20, 2016: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
Yixiang Zhu, Puyuan Xing, Junling Li
Lung cancer is the deadliest cancer in the worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of lung tumor diagnoses. Squamous cell lung cancer (SQCLC) is a common pathological type, almost 20%-30% of NSCLC. Surgery, chemotherapy, and molecular targeted therapies are the mainstay of treatment for patients with SQCLC. But most patients are diagnosed at advanced stage so that they miss the chance of operation. While noteworthy outcomes have improved with adenocarcinoma of lung with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), a therapeutic plateau for advanced squamous cell lung cancer patients are still not solved...
October 20, 2016: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
Jumpei Kashima, Yusuke Okuma, Maki Miwa, Yukio Hosomi
Brain metastases (BM) is one of the most crucial distant metastases in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. There is no consensus about which EGFR tyrosine kinase inhibitor (TKI) is most effective against BM in such patients. Here, we compared prognoses of patients with EGFR-TKI naïve EGFR-positive BM treated with erlotinib or gefitinib after BM diagnosis. Of 269 patients with NSCLC treated with EGFR-TKIs at a single institution, we reviewed medical records of 205 patients with documented EGFR mutations...
November 2016: Medical Oncology
Xiang-Jun Tang, Kuan-Ming Huang, Hui Gui, Jun-Jie Wang, Jun-Ti Lu, Long-Jun Dai, Li Zhang, Gang Wang
As one of the natural herbal flavonoids, myricetin has attracted much research interest, mainly owing to its remarkable anticancer properties and negligible side effects. It holds great potential to be developed as an ideal anticancer drug through improving its bioavailability. This study was performed to investigate the effects of Pluronic-based micelle encapsulation on myricetin-induced cytotoxicity and the mechanisms underlying its anticancer properties in human glioblastoma cells. Cell viability was assessed using a methylthiazol tetrazolium assay and a real-time cell analyzer...
2016: International Journal of Nanomedicine
Bernard Omolo, Mingli Yang, Fang Yin Lo, Michael J Schell, Sharon Austin, Kellie Howard, Anup Madan, Timothy J Yeatman
BACKGROUND: The KRAS gene is mutated in about 40 % of colorectal cancer (CRC) cases, which has been clinically validated as a predictive mutational marker of intrinsic resistance to anti-EGFR inhibitor (EGFRi) therapy. Since nearly 60 % of patients with a wild type KRAS fail to respond to EGFRi combination therapies, there is a need to develop more reliable molecular signatures to better predict response. Here we address the challenge of adapting a gene expression signature predictive of RAS pathway activation, created using fresh frozen (FF) tissues, for use with more widely available formalin fixed paraffin-embedded (FFPE) tissues...
October 19, 2016: BMC Medical Genomics
Lin Liu, PeiYu Huang, ZhiHui Wang, Nan Chen, Con Tang, Zhong Lin, PeiJian Peng
BACKGROUND: Previous studies have reported that eEF-2 kinase is associated with tumour cell sensitivity to certain therapies. In the present study, we investigated the relationship between eEF-2 kinase and lapatinib, a dual inhibitor of EGFR and HER-2, in nasopharyngeal carcinoma (NPC) cells. METHODS: The effect of treatment on the growth and proliferation of NPC cells was measured by three methods: cell counting, crystal violet staining and colony counting. Apoptosis was evaluated by flow cytometry to determine Annexin V-APC/7-AAD and cleaved PARP levels, and the results were further confirmed by Western blot analysis...
October 19, 2016: BMC Cancer
Qiuyi Zhang, Xuchao Zhang, Honghong Yan, Benyuan Jiang, Chongrui Xu, Jinji Yang, Zhihong Chen, Jian Su, Yi-Long Wu, Qing Zhou
BACKGROUND: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are remarkably effective for treating EGFR-mutant non-small cell lung cancer (NSCLC). However, the individual role of EGFR-TKIs in patients with brain metastasis (BM) arising from EGFR-mutant NSCLC remains unclear. METHODS: Patients with BM secondary to NSCLC and harboring EGFR-activating mutations were retrospectively screened. Patients who received gefitinib or erlotinib to control both extracranial lesions (ECLs) and intracranial lesions (ICLs) were eligible...
September 1, 2016: Thoracic Cancer
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