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https://www.readbyqxmd.com/read/28437852/a-diagnostic-microdosing-approach-to-investigate-platinum-sensitivity-in-non-small-cell-lung-cancer
#1
Si-Si Wang, Maike Zimmermann, Hongyong Zhang, Tzu-Yin Lin, Michael Malfatti, Kurt Haack, Kenneth W Turteltaub, George D Cimino, Ralph de Vere White, Chong-Xian Pan, Paul T Henderson
The platinum-based drugs cisplatin, carboplatin and oxaliplatin are often used for chemotherapy, but drug resistance is common. The prediction of resistance to these drugs via genomics is a challenging problem since hundreds of genes are involved. A possible alternative is to use mass spectrometry to determine the propensity for cells to form drug-DNA adducts-the pharmacodynamic drug-target complex for this class of drugs. The feasibility of predictive diagnostic microdosing was assessed in non-small cell lung cancer (NSCLC) cell culture and a pilot clinical trial...
April 24, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28436990/tcrp1-promotes-nih-3t3-cell-transformation-by-over-activating-pdk1-and-akt1
#2
C Wang, H Liu, Q Qiu, Z Zhang, Y Gu, Z He
Tongue cancer resistance-related protein 1 (TCRP1) gene was first cloned from the multidrug resistance tongue cancer cell (Tca8113/pingyangmycin) in our lab. Our precious studies demonstrated that TCRP1 was involving in chemotherapy and radiotherapy resistance of tongue cancer cells, lung cancer cells and ovarian cancer cells. In this study, we showed that TCRP1 overexpression promotes cell transformation and tumorigenesis through hyperphosphorylation of the oncogenic kinase 3-phosphoinositide-dependent protein kinase-1 (PDK1) and AKT1, whereas inhibition of PDK1 by OSU-03012 or PDK1 small interfering RNA reversed TCRP1-mediated cell transformation...
April 24, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28436422/rational-design-of-non-resistant-targeted-cancer-therapies
#3
Francisco Martínez-Jiménez, John P Overington, Bissan Al-Lazikani, Marc A Marti-Renom
Drug resistance is one of the major problems in targeted cancer therapy. A major cause of resistance is changes in the amino acids that form the drug-target binding site. Despite of the numerous efforts made to individually understand and overcome these mutations, there is a lack of comprehensive analysis of the mutational landscape that can prospectively estimate drug-resistance mutations. Here we describe and computationally validate a framework that combines the cancer-specific likelihood with the resistance impact to enable the detection of single point mutations with the highest chance to be responsible of resistance to a particular targeted cancer therapy...
April 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28435288/the-activity-safety-and-evolving-role-of-brigatinib-in-patients-with-alk-rearranged-non-small-cell-lung-cancers
#4
REVIEW
Joshua K Sabari, Fernando C Santini, Alison M Schram, Isabella Bergagnini, Ruqin Chen, Chebli Mrad, W Victoria Lai, Kathryn C Arbour, Alexander Drilon
Brigatinib (AP26113) is a dimethylphosphine oxide group-containing tyrosine kinase inhibitor (TKI) constructed around a bisanilinopyrimidine scaffold with potent activity against the anaplastic lymphoma kinase (ALK) and several other targets. Despite the activity of first- and second-generation ALK inhibitors in advanced ALK-rearranged lung cancers, the development of acquired resistance represents an ongoing challenge. Later generation ALK inhibitors such as brigatinib are important potential tools in the management of patients with acquired resistance characterized by continued dependency on ALK...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28435285/exploratory-cohort-study-and-meta-analysis-of-bim-deletion-polymorphism-in-patients-with-epidermal-growth-factor-receptor-mutant-non-small-cell-lung-cancer-treated-with-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitors
#5
Si Sun, Hui Yu, Huijie Wang, Xinmin Zhao, Xintai Zhao, Xianghua Wu, Jie Qiao, Jianhua Chang, Jialei Wang
BACKGROUND: Non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations might develop primary and secondary resistance to tyrosine kinase inhibitors (TKIs). The proapoptotic protein Bcl-2-like 11 (BIM) is a key modulator of apoptosis triggered by EGFR-TKIs. The recent studies have indicated that some patients with positive EGFR mutations were refractory to EGFR-TKIs if they harbored a BIM deletion polymorphism. The purpose of this study was to investigate whether BIM polymorphism predicts treatment efficacy of EGFR-TKIs in Chinese NSCLC patients...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28435028/antagonistic-effects-of-p53-and-hif1a-on-microrna-34a-regulation-of-ppp1r11-and-stat3-and-hypoxia-induced-epithelial-to-mesenchymal-transition-in-colorectal-cancer-cells
#6
Huihui Li, Matjaz Rokavec, Longchang Jiang, David Horst, Heiko Hermeking
BACKGROUND & AIMS: In colorectal tumors, hypoxia causes resistance to therapy and promotes metastasis. Loss of the tumor suppressor p53 (encoded by TP53) provides cancer cells with a selective advantage under conditions of hypoxia, but little is known about the mediators of this effect. METHODS: Isogenic CRC cell lines with different TP53 genotypes were placed under conditions of hypoxia. We examined the effects on levels and activity of microRNA-34 a (MIR34A) in CRC cells...
April 20, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28434399/the-next-generation-of-immunotherapy-keeping-lung-cancer-in-check
#7
REVIEW
Ashwin Somasundaram, Timothy F Burns
Lung cancer is the deadliest malignancy with more cancer deaths per year than the next three cancers combined. Despite remarkable advances in targeted therapy, advanced lung cancer patients have not experienced a significant improvement in mortality. Lung cancer has been shown to be immunogenic and responsive to checkpoint blockade therapy. Checkpoint signals such as CTLA-4 and PD-1/PD-L1 dampen T cell activation and allow tumors to escape the adaptive immune response. Response rates in patients with pretreated, advanced NSCLC were much higher and more durable with PD-1 blockade therapy compared to standard-of-care, cytotoxic chemotherapy...
April 24, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28433077/development-and-clinical-utility-of-a-blood-based-test-service-for-the-rapid-identification-of-actionable-mutations-in-non-small-cell-lung-carcinoma
#8
Hestia Mellert, Trudi Foreman, Leisa Jackson, Dianna Maar, Scott Thurston, Kristina Koch, Amanda Weaver, Samantha Cooper, Nicholas Dupuis, Ubaradka G Sathyanarayana, Jakkie Greer, Westen Hahn, Dawne Shelton, Paula Stonemetz, Gary A Pestano
Nearly 80% of cancer patients do not have genetic mutation results available at initial oncology consultation; up to 25% of patients begin treatment before receiving their results. These factors hinder the ability to pursue optimal treatment strategies. This study validates a blood-based genome-testing service that provides accurate results within 72 hours. We focused on targetable variants in advanced non-small cell lung carcinoma-epidermal growth factor receptor gene (EGFR) variant L858R, exon 19 deletion (ΔE746-A750), and T790M; GTPase Kirsten ras gene (KRAS) variants G12C/D/V; and echinoderm microtubule associated protein like and 4 anaplastic lymphoma receptor tyrosine kinase fusion (EML4-ALK) transcripts 1/2/3...
May 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/28431562/effects-of-the-common-polymorphism-in-the-human-aldehyde-dehydrogenase-2-aldh2-gene-on-the-lung
#9
Aoi Kuroda, Ahmed E Hegab, Gao Jingtao, Shuji Yamashita, Nobuyuki Hizawa, Tohru Sakamoto, Hideyasu Yamada, Satoshi Suzuki, Makoto Ishii, Ho Namkoong, Takanori Asakura, Mari Ozaki, Hiroyuki Yasuda, Junko Hamamoto, Shizuko Kagawa, Kenzo Soejima, Tomoko Betsuyaku
BACKGROUND: Aldehyde dehydrogenases (ALDHs) play a major role in detoxification of aldehydes. High expression of ALDHs is a marker for stem cells of many organs including the lungs. A common polymorphism in ALDH2 gene (ALDH2*2) results in inactivation of the enzyme and is associated with alcohol flushing syndrome and increased risk for cardiovascular and Alzheimer's diseases and some cancers. The effect of this ALDH2 polymorphism on the lung and its stem cells has not been thoroughly examined...
April 21, 2017: Respiratory Research
https://www.readbyqxmd.com/read/28431392/characterization-of-aurora-a-and-its-impact-on-the-effect-of-cisplatin-based-chemotherapy-in-patients-with-non-small-cell-lung-cancer
#10
Peng Kuang, Zuhua Chen, JiaYuan Wang, Zhentao Liu, Jingyuan Wang, Jing Gao, Lin Shen
BACKGROUND AND OBJECTIVE: Aurora A, as a member of serine/threonine kinase family and a common characteristic of epithelial cancers, plays a critical role in cell mitosis. However, the clinical significance of Aurora A in non-small cell lung cancer (NSCLC) remains undetermined. METHODS: The expression of Aurora A in NSCLC and paired normal adjacent lung tissues was determined by immunohistochemistry, Western blot, and reverse transcriptase polymerase chain reaction...
April 18, 2017: Translational Oncology
https://www.readbyqxmd.com/read/28431340/first-macrocyclic-3-rd-generation-alk-inhibitor-for-treatment-of-alk-ros1-cancer-clinical-and-designing-strategy-update-of-lorlatinib
#11
REVIEW
Sulman Basit, Zaman Ashraf, Kwangho Lee, Muhammad Latif
Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to 2(nd)-generation ALK inhibitors. Lorlatinib (PF-06463922) (6) is a 3(rd)-generation macrocyclic ALK-TKI that demonstrates many advantages over 2(nd)-generation ALK inhibitors. Lorlatinib has demonstrated decent kinase selectivity, promising pharmacokinetic profile, selective brain-penetration and strong antiproliferative activity in several ALK/ROS1-driven tumor models. The current review describes the activity spectrum, key events from discovery to clinical applications and the evidences that lorlatinib acts as an ALK/ROS1 inhibitor in clinical settings...
April 13, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28430586/epidermal-growth-factor-receptor-egfr-a-rising-star-in-the-era-of-precision-medicine-of-lung-cancer
#12
REVIEW
Xiaomin Liu, Ping Wang, Caiyan Zhang, Zhongliang Ma
Lung cancer is a leading cause of cancer mortality worldwide. In tumors, the important role of noncoding RNA regulatory networks has been more and more reveal. EGFR has been identified as an oncogenic driver of NSCLC, especially activating mutations EGFR and its inhibition with specific TKIs can generate dramatic tumor responses. Studies have shown that EGFR plays significant roles in the progression of NSCLC. Subset analysis of the small proportion of patients with EGFR-mutant lung cancer showed a disease-free survival benefit, but was underpowered to detect a survival advantage...
April 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28429795/cd200-positive-cancer-associated-fibroblasts-augment-the-sensitivity-of-epidermal-growth-factor-receptor-mutation-positive-lung-adenocarcinomas-to-egfr-tyrosine-kinase-inhibitors
#13
Masayuki Ishibashi, Shinya Neri, Hiroko Hashimoto, Tomoyuki Miyashita, Tatsuya Yoshida, Yuka Nakamura, Hibiki Udagawa, Keisuke Kirita, Shingo Matsumoto, Shigeki Umemura, Kiyotaka Yoh, Seiji Niho, Masahiro Tsuboi, Kenkichi Masutomi, Koichi Goto, Atsushi Ochiai, Genichiro Ishii
Cancer associated fibroblasts (CAFs) play important roles in the chemotherapeutic process, especially through influencing the resistance of tumor cells to molecular targeted therapy. Here we report the existence of a special subpopulation of patient-specific-CAFs that augment the sensitivity of EGFR gene mutation-positive lung cancer to the EGFR-tyrosine kinase inhibitor (EGFR-TKI), gefitinib. When cocultured with EGFR mutation positive lung cancer cells, these CAFs increased the apoptic effect of gefitinib on cancer cells, whereas, in the absence of gefitinib, they did not affect cancer cell viability...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28428274/egfr-mediates-responses-to-small-molecule-drugs-targeting-oncogenic-fusion-kinases
#14
Aria Vaishnavi, Laura Schubert, Uwe Rix, Lindsay A Marek, Anh T Le, Stephen Keysar, Magdalena J Glogowska, Matthew A Smith, Severine L Kako, Natalia J Sumi, Kurtis D Davies, Kathryn E Ware, Marileila Varella-Garcia, Eric B Haura, Antonio Jimeno, Lynn E Heasley, Dara L Aisner, Robert C Doebele
Oncogenic kinase fusions of ALK, ROS1, RET and NTRK1 act as drivers in human lung and other cancers. Residual tumor burden following treatment of ALK or ROS1+ lung cancer patients with oncogene-targeted therapy ultimately enables the emergence of drug-resistant clones, limiting the long-term effectiveness of these therapies. To determine the signaling mechanisms underlying incomplete tumor cell killing in oncogene-addicted cancer cells, we investigated the role of EGFR signaling in drug-naive cancer cells harboring these oncogene fusions...
April 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/28428090/preparation-and-characterization-of-lipid-nanoparticle-pdna-complexes-for-stat3-downregulation-and-overcoming-chemotherapy-resistance-in-lung-cancer-cells
#15
Mustafa Kotmakçı, Vildan Bozok Çetintaş, A Gülten Kantarcı
Developments in the field of molecular oncology have revealed that resistance to chemotherapeutics is acqured through several mechanisms including overexpression of common oncogenic proteins. Signal Transducer and Activator of Transcription 3 (STAT3) is one of these oncogenes that is overexpressed in many cancer types. RNA interference (RNAi) is proven powerful tool for downregulating STAT3, allowing re-sensitization of resistant cancer cells. However, delivery of RNA interference-mediating molecules for STAT3 downregulation in lung cancer cells is limited to a small number of studies most of which employ commercially available transfection kits...
April 18, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28427199/combinatorial-treatment-with-polyi-c-and-anti-il6-enhances-apoptosis-and-suppresses-metastasis-of-lung-cancer-cells
#16
Wai Hoe Lau, Xiphias Ge Zhu, Shamaine Wei Ting Ho, Shu Chun Chang, Jeak Ling Ding
Activation of TLR3 stimulates cancer cell apoptosis and triggers secretion of inflammatory cytokines. PolyI:C, a TLR3 agonist, activates immune cells and regresses metastatic lung cancer in vivo. Although polyI:C reportedly kills lung carcinomas, the mechanism remains elusive. Here, we demonstrated that polyI:C suppressed the proliferation and survival of metastatic (NCI-H358 and NCI-H292) and non-metastatic (A549) lung cancer cells. Notably, A549, NCI-H292 and NCI-H358 which are inducible by polyI:C, expressed low-to-medium level of TLR3 protein, and were susceptible to polyI:C treatment...
March 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28427045/mir-142-3p-overexpression-increases-chemo-sensitivity-of-nsclc-by-inhibiting-hmgb1-mediated-autophagy
#17
Yuqing Chen, Xin Zhou, Jianou Qiao, Aihua Bao
BACKGROUND: Non-small-cell lung cancer (NSCLC) is a deadly cancer with high mortality rate. Drug resistance represents a main obstacle in NSCLC treatment. High mobility group box-1 (HMGB1) protein promotes drug resistance in NSCLC cells by activating protective autophagy. METHODS: In the current study, we investigated the regulatory role of microRNA-142-3p (miR-142-3p) in HMGB1-mediated autophagy of NSCLC cells and its impact on drug resistance of NSCLC in vitro and in vivo...
March 16, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28427013/the-accelerated-path-of-ceritinib-translating-pre-clinical-development-into-clinical-efficacy
#18
REVIEW
Tony S K Mok, Lucio Crino, Enriqueta Felip, Ravi Salgia, Tommaso De Pas, Daniel S W Tan, Laura Q M Chow
The discovery of anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) in 2007 led to the development and subsequent approval of the ALK inhibitor crizotinib in 2011. However, despite its clinical efficacy, resistance to crizotinib invariably develops. There is now a next generation of ALK inhibitors, including two that have been approved-ceritinib and alectinib-and others that are in development-brigatinib, lorlatinib and X-396. Ceritinib and the other next-generation ALK inhibitors are more potent than crizotinib and can overcome tumor cell resistance mechanisms...
March 30, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28426996/design-synthesis-sar-discussion-in%C3%A2-vitro-and-in%C3%A2-vivo-evaluation-of-novel-selective-egfr-modulator-to-inhibit-l858r-t790m-double-mutants
#19
Haoyang Zhang, Wenkui Wu, Chao Feng, Zhaogang Liu, Enhe Bai, Xueyuan Wang, Meng Lei, Hao Cheng, Huayun Feng, Jingmiao Shi, Jia Wang, Zhao Zhang, Tao Jin, Shanshan Chen, Shihe Hu, Yongqiang Zhu
Based upon the modeling binding mode of marketed AZD9291 with T790M, a series of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline derivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound 8 showed excellent enzyme inhibitory activities and selectivity with sub nanomolar IC50 values for both the single L858R and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound 8 exhibited good microsomes stabilities and pharmacokinetic properties and lower binding affinity to hERG ion channel than AZD9291 and displayed strong antiproliferative activity against the H1975 non-small cell lung cancer (NSCLC) cells bearing T790M/L858R and in vivo anticancer efficacy in a human NSCLC (H1975) xenograft mouse model...
April 14, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28425853/evaluation-of-the-in-vitro-chemosensitivity-and-correlation-with-clinical-outcomes-in-lung-cancer-using-the-atp-tca
#20
Zhiyao Chen, Shichao Zhang, Sheng Ma, Chang Li, Chun Xu, Yinfang Shen, Jun Zhao, Liyan Miao
BACKGROUND AND OBJECTIVE: Multiple drug resistance (MDR) to chemotherapeutic agents often leads to a failure to respond to chemotherapy. We utilized an in vitro chemosensitivity test to identify sensitive and effective chemotherapeutic drugs and further elucidated the correlation between the in vivo chemosensitivity and clinical outcomes. METHODS: Here, we evaluated the in vitro chemosensitivity and MDR of 120 lung cancer patients to eight single-drug chemotherapies and of 291 lung cancer patients to seven chemotherapy regimens using an ATP-based tumour chemosensitivity assay (ATP-TCA)...
April 19, 2017: Anti-cancer Agents in Medicinal Chemistry
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