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Ysabella Z A Van Sebille, Rachel J Gibson, Hannah R Wardill, Kate R Secombe, Imogen A Ball, Dorothy M K Keefe, John W Finnie, Joanne M Bowen
Dacomitinib - an irreversible pan-ErbB tyrosine kinase inhibitor (TKI) - causes diarrhoea in 75% of patients. Dacomitinib-induced diarrhoea has not previously been investigated and the mechanisms remain poorly understood. The present study aimed to develop an in-vitro and in-vivo model of dacomitinib-induced diarrhoea to investigate underlying mechanisms. T84 cells were treated with 1-4 μM dacomitinib and resistance and viability were measured using transepithelial electrical resistance (TEER) and XTT assays...
March 17, 2017: International Journal of Cancer. Journal International du Cancer
Dong-Wan Kim, Edward B Garon, Aminah Jatoi, Dorothy M Keefe, Mario E Lacouture, Stephen Sonis, Diana Gernhardt, Tao Wang, Nagdeep Giri, Jim P Doherty, Sashi Nadanaciva, Joseph O'Connell, Eric Sbar, Byoung Chul Cho
OBJECTIVES: Dacomitinib is a pan-HER inhibitor for advanced non-small-cell lung cancer (NSCLC). We explored the impact of a planned 4-day dacomitinib dose interruption on plasma exposure of dacomitinib and adverse events (AEs) of interest in Cohort III of the ARCHER 1042 study. MATERIALS AND METHODS: Patients, treatment-naïve for advanced NSCLC with EGFR activating mutations, received oral dacomitinib 45mg QD (once daily). A planned dose interruption occurred in Cycle 1 from Days 11 through 14...
April 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Lei Xu, Huini Wu, Chao Jiang, Hongcai Wang, Bei Gao, Shumei Yan, Yushu Qi, Shufeng Zhou
OBJECTIVE: Aberrant epidermal growth factor receptor (EGFR) is involved in a variety of cancers and its inhibitors have been studied for over a decade. We aim to investigate the effects of dacomitinib, a second generation pan-EGFR inhibitor, on ovarian cancer cells. METHODS: By immunohistochemistry, we studied the clinical significance of EGFR expression in epithelial ovarian cancer (EOC). The correlations between EGFR expression and the clinicopathological variables of patients with EOC were assessed using Pearson's X2 test...
November 2016: Discovery Medicine
Haijun Zhang
Lung cancer, ~80%-85% of which is non-small-cell lung cancer (NSCLC), is the leading cause of cancer-related mortality worldwide. Sensitizing mutations in epidermal growth factor receptor (EGFR) gene (EGFRm(+)), such as exon 19 deletions and exon 21 L858R point mutations, are the most important drivers in NSCLC patients. In this respect, small-molecule EGFR tyrosine kinase inhibitors (TKIs) have been designed and developed, which launched the era of targeted, personalized and precise medicine for lung cancer...
2016: Drug Design, Development and Therapy
Yoshihisa Kobayashi, Koichi Azuma, Hiroki Nagai, Young Hak Kim, Yosuke Togashi, Yuichi Sesumi, Masato Chiba, Masaki Shimoji, Katsuaki Sato, Kenji Tomizawa, Toshiki Takemoto, Kazuto Nishio, Tetsuya Mitsudomi
Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKIs). We previously reported that tumors with exon 18 mutations are particularly sensitive to irreversible second-generation (2G) afatinib compared with 1G-TKIs. However, data on the mechanisms of acquired resistance to afatinib are limited. We established afatinib-resistant cells by transfecting Ba/F3 cells with common or exon 18 (G719A and Del18) mutations and subjecting them to chronic exposure to increasing concentrations of afatinib...
December 2, 2016: Molecular Cancer Therapeutics
Emiliano Calvo, Jean-Charles Soria, Wen Wee Ma, Tao Wang, Rastilav Bahleda, Anthony W Tolcher, Diana Gernhardt, Joseph O'Connell, Robert Millham, Nagdeep Giri, Michael J Wick, Alex A Adjei, Manuel Hidalgo
Purpose: This phase I, open-label, single-arm trial assessed the safety and tolerability of dacomitinib-figitumumab combination therapy in patients with advanced solid tumors.Experimental Design: A standard 3 + 3 dose escalation/de-escalation design was utilized. Starting doses were figitumumab 20 mg/kg administered intravenously once every 3 weeks and dacomitinib 30 mg administered orally once daily. We also performed an independent study of the combination in patient-derived xenograft (avatar mouse) models of adenoid cystic carcinoma...
October 12, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Jun Chen, Taisei Kinoshita, Juthamas Sukbuntherng, Betty Y Chang, Laurence Elias
Ibrutinib is a potent, small-molecule Bruton tyrosine kinase (BTK) inhibitor developed for the treatment of B-cell malignancies. Ibrutinib covalently binds to Cys481 in the ATP-binding domain of BTK. This cysteine residue is conserved among 9 other tyrosine kinases, including HER2 and EGFR, which can be targeted. Screening large panels of cell lines demonstrated that ibrutinib was growth inhibitory against some solid tumor cells, including those inhibited by other HER2/EGFR inhibitors. Among sensitive cell lines, breast cancer lines with HER2 overexpression were most potently inhibited by ibrutinib (<100 nmol/L); in addition, the IC50s were lower than that of lapatinib and dacomitinib...
December 2016: Molecular Cancer Therapeutics
Ah-Rong Nam, Ji-Won Kim, Yongjun Cha, Hyerim Ha, Ji Eun Park, Ju-Hee Bang, Mei Hua Jin, Kyung-Hun Lee, Tae-Yong Kim, Sae-Won Han, Seock-Ah Im, Tae-You Kim, Do-Youn Oh, Yung-Jue Bang
Currently, there is no validated therapeutic target for biliary tract cancer (BTC). This study aimed to investigate the pre-clinical and clinical implication of HER2 as a therapeutic target in BTC. We established two novel HER2-amplified BTC cell lines, SNU-2670 and SNU-2773, from gallbladder cancer patients. SNU-2670 and SNU-2773 cells were sensitive to trastuzumab, dacomitinib, and afatinib compared with nine HER2-negative BTC cell lines. Dacomitinib and afatinib led to G1 cell cycle arrest in SNU-2773 cells and apoptosis in SNU-2670 cells...
September 6, 2016: Oncotarget
Jeff B Smaill, Andrea J Gonzales, Julie A Spicer, Helen Lee, Jessica E Reed, Karen Sexton, Irene W Althaus, Tong Zhu, Shannon L Black, Adrian Blaser, William A Denny, Paul A Ellis, Stephen Fakhoury, Patricia J Harvey, Ken Hook, Florence O J McCarthy, Brian D Palmer, Freddy Rivault, Kevin Schlosser, Teresa Ellis, Andrew M Thompson, Erin Trachet, R Thomas Winters, Haile Tecle, Alexander Bridges
Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of quinazoline- and pyrido[3,4-d]pyrimidine-based analogues of the irreversible pan-erbB inhibitor, canertinib. Cyclic amine bearing crotonamides were determined to provide rapid inhibition of cellular erbB1 autophosphorylation and good metabolic stability in liver microsome and hepatocyte assays. The influence of 4-anilino substitution on pan-erbB inhibitory potency was investigated. Several anilines were identified as providing potent, reversible pan-erbB inhibition...
September 8, 2016: Journal of Medicinal Chemistry
Martina Tilio, Valentina Gambini, Junbiao Wang, Chiara Garulli, Cristina Kalogris, Cristina Andreani, Caterina Bartolacci, Maria Elexpuru Zabaleta, Lucia Pietrella, Albana Hysi, Manuela Iezzi, Barbara Belletti, Fiorenza Orlando, Mauro Provinciali, Roberta Galeazzi, Cristina Marchini, Augusto Amici
HER2 tyrosine kinase receptor is a validated target in breast cancer therapy. However, increasing evidence points to a major role of Δ16HER2 splice variant commonly coexpressed with HER2 and identified as a clinically important HER2 molecular alteration promoting aggressive metastatic breast cancer. Consistently, mice transgenic for the human Δ16HER2 isoform (Δ16HER2 mice) develop invasive mammary carcinomas with early onset and 100% penetrance. The present study provides preclinical evidence that Δ16HER2 expression confers de novo resistance to standard anti-HER2-therapies such as Lapatinib and acquired resistance to the selective Src inhibitor Saracatinib in breast cancer...
October 10, 2016: Cancer Letters
Amy Prawira, Irene Brana-Garcia, Anna Spreafico, Andrew Hope, John Waldron, Albiruni R Abdul Razak, Eric X Chen, Raymond Jang, Brian O'Sullivan, Meredith Giuliani, Andrew Bayley, John Cho, Lisa Wang, Bayardo Perez-Ordonez, Ilan Weinreb, Lillian L Siu, Aaron R Hansen
Background Curative-intent, non-surgical treatment options for locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) include radiotherapy with/without chemotherapy or radiotherapy with cetuximab. This single institution phase I dose escalation trial tested the pan-human epidermal growth factor receptor (HER) oral tyrosine kinase inhibitor, dacomitinib, in combination with standard cisplatin-based chemoradiotherapy. Methods Patients received oral dacomitinib once daily at 3 protocol-defined dose levels (15 mg, 30 mg, and 45 mg)...
October 2016: Investigational New Drugs
S S Ramalingam, K O'Byrne, M Boyer, T Mok, P A Jänne, H Zhang, J Liang, I Taylor, E I Sbar, L Paz-Ares
No abstract text is available yet for this article.
July 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Olgun Elicin, Mahmut Ozsahin
INTRODUCTION: Recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) has a dismal prognosis. With the emergence of monoclonal antibodies and tyrosine kinase inhibitors (TKI) targeting the epidermal growth factor receptor (EGFR), several drugs were developed and tested in HNSCC. To date, the monoclonal antibody cetuximab is the only approved therapy for curative and recurrent/metastatic patients. Other EGFR-targeting drugs either failed in the clinical trials or are still in the early phases of drug development and research...
June 2016: Expert Opinion on Investigational Drugs
Petra Martin, Erin Stewart, Nhu-An Pham, Celine Mascaux, Devang Panchal, Ming Li, Lucia Kim, Shingo Sakashita, Dennis Wang, Jenna Sykes, Thomas Friess, Frances A Shepherd, Geoffrey Liu, Ming-Sound Tsao
BACKGROUND: The epidermal growth factor receptor (EGFR) kinase domain T790M (amino acid substitution at position 790 in EGFR from threonine [T] to methionine [M]) mutation in non-small-cell lung cancer (NSCLC) results in resistance to EGFR tyrosine kinase inhibitors (TKIs). We used a patient-derived tumor xenograft (PDX) model containing an EGFR exon 19 deletion/T790M mutation to assess response to the EGFR-directed antibody cetuximab. Changes in the EGFR signaling pathway and ligand expression after treatment were investigated...
January 22, 2016: Clinical Lung Cancer
Pasi A Jänne, Alice T Shaw, D Ross Camidge, Giuseppe Giaccone, S Martin Shreeve, Yiyun Tang, Zelanna Goldberg, Jean-François Martini, Huiping Xu, Leonard P James, Benjamin J Solomon
INTRODUCTION: This phase I study investigated the activity of the irreversible pan-human epidermal growth factor receptor inhibitor dacomitinib in combination with the mesenchymal-epithelial transition factor/anaplastic lymphoma kinase/ROS proto-oncogene 1, receptor tyrosine kinase inhibitor crizotinib in advanced non-small cell lung cancer. METHODS: Patients with progression after at least one line of chemotherapy or targeted therapy received dacomitinib once daily and crizotinib once daily or twice daily, with doses escalated until intolerable toxicity; the expansion cohorts received the maximum tolerated dose of the combination...
May 2016: Journal of Thoracic Oncology
Kie Kyon Huang, Kang Won Jang, Sangwoo Kim, Han Sang Kim, Sung-Moo Kim, Hyeong Ju Kwon, Hye Ryun Kim, Hwan Jung Yun, Myung Ju Ahn, Keon Uk Park, Kalpana Ramnarayanan, John R McPherson, Shenli Zhang, Je-Keun Rhee, André L Vettore, Kakoli Das, Takatsugu Ishimoto, Joo Hang Kim, Yoon Woo Koh, Se Hun Kim, Eun Chang Choi, Bin Tean Teh, Steven G Rozen, Tae-Min Kim, Patrick Tan, Byoung Chul Cho
Dacomitinib, an irreversible pan-HER inhibitor, had shown modest clinical activity in squamous cell carcinoma of head and neck (SCCHN) patients. Therefore, validated predictive biomarkers are required to identify patients most likely to benefit from this therapeutic option. To characterize the genetic landscape of cisplatin-treated SCCHN genomes and identify potential predictive biomarkers for dacomitinib sensitivity, we performed whole exome sequencing on 18 cisplatin-resistant metastatic SCCHN tumors and their matched germline DNA...
January 21, 2016: Scientific Reports
Do-Youn Oh, Kewn-Wook Lee, Jae Yong Cho, Won Ki Kang, Seock-Ah Im, Jin Won Kim, Yung-Jue Bang
BACKGROUND: Dacomitinib, an irreversible panHER inhibitor, shows significant preclinical antitumor activity in human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). The aim of this study was to evaluate the clinical activity of dacomitinib and discover potential biomarkers in HER2-positive GC patients. METHODS: We enrolled previously treated advanced HER2-positive GC [HER2 FISH (+) or HER2 IHC 3+] patients. The patients received dacomitinib 45 mg once daily...
October 2016: Gastric Cancer
Yufang Ma, Nan Tang, Reid C Thompson, Bret C Mobley, Steven W Clark, Jann N Sarkaria, Jialiang Wang
PURPOSE: Aberrant activation of EGFR is a hallmark of glioblastoma. However, EGFR inhibitors exhibit at best modest efficacy in glioblastoma. This is in sharp contrast with the observations in EGFR-mutant lung cancer. We examined whether activation of functionally redundant receptor tyrosine kinases (RTKs) conferred resistance to EGFR inhibitors in glioblastoma. EXPERIMENTAL DESIGN: We collected a panel of patient-derived glioblastoma xenograft (PDX) lines that maintained expression of wild-type or mutant EGFR in serial xenotransplantation and tissue cultures...
April 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Sai-Hong Ignatius Ou, Ross A Soo
EGFR tyrosine-kinase inhibitors (TKIs) have now been firmly established as the first-line treatment for non-small-cell lung cancer (NSCLC) patients harboring activating EGFR mutations, based on seven prospective randomized Phase III trials. However, despite significantly improved overall response rate and improved median progression-free survival when compared to platinum-doublet chemotherapy, EGFR-mutant NSCLC patients treated with EGFR TKIs invariably progress due to the emergence of acquired resistances, with the gatekeeper T790M mutation accounting for up to 60% of the resistance mechanisms...
2015: Drug Design, Development and Therapy
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