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https://www.readbyqxmd.com/read/28676215/identification-of-a-novel-t1151k-alk-mutation-in-a-patient-with-alk-rearranged-nsclc-with-prior-exposure-to-crizotinib-and-ceritinib
#1
Viola W Zhu, J Jean Cui, Maria Fernandez-Rocha, Alexa B Schrock, Siraj M Ali, Sai-Hong Ignatius Ou
Patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) derive significant clinic benefit from treatment with ALK inhibitors. Crizotinib was the first approved tyrosine kinase inhibitor (TKI) for this distinct molecular subset of NSCLC. Disease progression on TKI inevitably arises secondary to diverse resistance mechanisms among which emergence of secondary ALK mutations is one of many ways in which tumor cells have adapted to survive. Therefore there is a clinical imperative to identify acquired ALK mutations via repeat tissue biopsy if clinically feasible...
August 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28628492/complete-remission-of-intrathecal-metastases-with-lorlatinib-therapy-in-a-heavily-pretreated-alk-positive-lung-cancer-patient
#2
Maximilian J Hochmair, Sophia Schwab, Helmut Prosch
Patients with lung cancer who show EML4-ALK translocation are routinely treated with ALK tyrosine kinase inhibitors, although in the majority of cases, these patients develop resistance over time. The central nervous system is a common of site of recurrence in this population, which calls for next-generation drugs that can penetrate into the brain and achieve clinically meaningful central nervous system activity. Here, I report the case of a female patient diagnosed with adenocarcinoma of the lung in 2005, at the age of 46 years, who underwent lobectomy and then experienced a series of progression episodes 6 years later...
June 16, 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/28594000/synthesis-and-preliminary-pet-imaging-of-11-c-and-18-f-isotopologues-of-the-ros1-alk-inhibitor-lorlatinib
#3
Thomas Lee Collier, Marc D Normandin, Nickeisha A Stephenson, Eli Livni, Steven H Liang, Dustin W Wooten, Shadi A Esfahani, Michael G Stabin, Umar Mahmood, Jianqing Chen, Wei Wang, Kevin Maresca, Rikki N Waterhouse, Georges El Fakhri, Paul Richardson, Neil Vasdev
Lorlatinib (PF-06463922) is a next-generation small-molecule inhibitor of the orphan receptor tyrosine kinase c-ros oncogene 1 (ROS1), which has a kinase domain that is physiologically related to anaplastic lymphoma kinase (ALK), and is undergoing Phase I/II clinical trial investigations for non-small cell lung cancers. An early goal is to measure the concentrations of this drug in brain tumour lesions of lung cancer patients, as penetration of the blood-brain barrier is important for optimal therapeutic outcomes...
June 8, 2017: Nature Communications
https://www.readbyqxmd.com/read/28465216/ros1-protein-tyrosine-kinase-inhibitors-in-the-treatment-of-ros1-fusion-protein-driven-non-small-cell-lung-cancers
#4
REVIEW
Robert Roskoski
ROS1 protein-tyrosine kinase fusion proteins are expressed in 1-2% of non-small cell lung cancers. The ROS1 fusion partners include CD74, CCDC6, EZR, FIG, KDELR2, LRIG3, MSN, SDC4, SLC34A2, TMEM106B, TMP3, and TPD52L1. Physiological ROS1 is closely related to the ALK, LTK, and insulin receptor protein-tyrosine kinases. ROS1 is a so-called orphan receptor because the identity of its activating ligand, if any, is unknown. The receptor is expressed during development, but little is expressed in adults and its physiological function is unknown...
April 30, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
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
#5
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...
July 7, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28427013/the-accelerated-path-of-ceritinib-translating-pre-clinical-development-into-clinical-efficacy
#6
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...
April 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28285684/dual-occurrence-of-alk-g1202r-solvent-front-mutation-and-small-cell-lung-cancer-transformation-as-resistance-mechanisms-to-second-generation-alk-inhibitors-without-prior-exposure-to-crizotinib-pitfall-of-solely-relying-on-liquid-re-biopsy
#7
Sai-Hong Ignatius Ou, Thomas K Lee, Lauren Young, Maria Y Fernandez-Rocha, Dean Pavlick, Alexa B Schrock, Viola W Zhu, Jeffrey Milliken, Siraj M Ali, Barbara J Gitlitz
Development of the acquired ALK G1202R solvent front mutation and small cell lung cancer (SCLC) transformation have both been independently reported as resistance mechanisms to ALK inhibitors in ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) patients but have not been reported in the same patient. Here we report an ALK+ NSCLC patient who had disease progression after ceritinib and then alectinib where an ALK G1202R mutation was detected on circulating tumor (ct) DNA prior to enrollment onto a trial of another next generation ALK inhibitor, lorlatinib...
April 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28245558/l1198f-mutation-resensitizes-crizotinib-to-alk-by-altering-the-conformation-of-inhibitor-and-atp-binding-sites
#8
Jian Li, Rong Sun, Yuehong Wu, Mingzhu Song, Jia Li, Qianye Yang, Xiaoyi Chen, Jinku Bao, Qi Zhao
The efficacy of anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer (NSCLC) treatment with small molecule inhibitors is greatly challenged by acquired resistance. A recent study reported the newest generation inhibitor resistant mutation L1198F led to the resensitization to crizotinib, which is the first Food and Drug Administration (FDA) approved drug for the treatment of ALK-positive NSCLC. It is of great importance to understand how this extremely rare event occurred for the purpose of overcoming the acquired resistance of such inhibitors...
February 24, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27888620/identification-of-different-alk-mutations-in-a-pair-of-neuroblastoma-cell-lines-established-at-diagnosis-and-relapse
#9
Lindi Chen, Angharad Humphreys, Lisa Turnbull, Angela Bellini, Gudrun Schleiermacher, Helen Salwen, Susan L Cohn, Nick Bown, Deborah A Tweddle
Anaplastic Lymphoma Kinase (ALK) is a transmembrane receptor kinase that belongs to the insulin receptor superfamily and has previously been shown to play a role in cell proliferation, migration and invasion in neuroblastoma. Activating ALK mutations are reported in both hereditary and sporadic neuroblastoma tumours, and several ALK inhibitors are currently under clinical evaluation as novel treatments for neuroblastoma. Overall, mutations at codons F1174, R1275 and F1245 together account for ~85% of reported ALK mutations in neuroblastoma...
December 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/27693947/identification-of-non-resistant-ros-1-inhibitors-using-structure-based-pharmacophore-analysis
#10
Disha Pathak, Navriti Chadha, Om Silakari
Proto-oncogene receptor tyrosine kinase ROS-1 plays a key role in regulating a variety of cancers mainly non-small cell lung cancer (NSCLC). The marketed ROS-1 inhibitors such as Crizotinib suffer from the tribulations of growing resistance due to mutations primarily Gly2032Arg in the ROS-1 protein. To curb the problem of resistance, researchers have developed inhibitors such as Lorlatinib against the mutant protein. The present study was designed to identify inhibitors against wild type (WT) as well as mutant ROS-1 protein that will offer a broader spectrum of activity...
November 2016: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/27693505/drug-resistance-in-alk-positivenon-small-cell-lungcancer-patients
#11
REVIEW
Mengjia Qian, Bijun Zhu, Xiangdong Wang, Michael Liebman
Patients are diagnosed as anaplastic lymphoma kinase (ALK) positive, i.e. exhibiting the ALK rearrangement, and comprise 3-7% of non-small-cell lung cancer (NSCLC) cases. Three generations of ALK inhibitors have been developed and used in targeted therapy, although there are still improving spaces of drug resistance at the initiation of each treatment. The current review discusses the pathophysiology of ALK-positive NSCLC and the role of three generations of ALK target inhibitors including crizotinib, ceritinib, alectinib and lorlatinib, as well as the mechanisms of the secondary resistance...
April 2017: Seminars in Cell & Developmental Biology
https://www.readbyqxmd.com/read/27682212/current-and-developing-therapies-for-the-treatment-of-non-small-cell-lung-cancer-with-alk-abnormalities-update-and-perspectives-for-clinical-practice
#12
REVIEW
M Caccese, R Ferrara, S Pilotto, L Carbognin, G Grizzi, A Caliò, M Brunelli, F Cuppone, S Petraglia, A Scarpa, G Tortora, E Bria
The treatment of patients with ALK-rearranged non-small-cell lung cancer was completely revolutionized by the introduction of Crizotinib, a small molecule inhibiting ALK, MET and ROS1. Given that resistance occurs within approximately 12 months, in order to develop more potent inhibitors and to increase drug penetration to CNS, innovative ALK-inhibitors were developed. Second-generation ALK inhibitors Ceritinib (LDK378), Alectinib (CH5424802/RO5424802) and Brigatinib (AP26113) have shown significant clinical activity, and were rapidly approved by regulatory agencies...
December 2016: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/27662658/synergistic-activity-of-alk-and-mtor-inhibitors-for-the-treatment-of-npm-alk-positive-lymphoma
#13
Sara Redaelli, Monica Ceccon, Laura Antolini, Roberta Rigolio, Alessandra Pirola, Marco Peronaci, Carlo Gambacorti-Passerini, Luca Mologni
ALK-positive Anaplastic Large Cell Lymphoma (ALCL) represents a subset of Non-Hodgkin Lymphoma whose treatment benefited from crizotinib development, a dual ALK/MET inhibitor. Crizotinib blocks ALK-triggered pathways such as PI3K/AKT/mTOR, indispensable for survival of ALK-driven tumors.Despite the positive impact of targeted treatment in ALCL, resistant clones are often selected during therapy. Strategies to overcome resistance include the design of second generation drugs and the use of combined therapies that simultaneously target multiple nodes essential for cells survival...
November 8, 2016: Oncotarget
https://www.readbyqxmd.com/read/27432227/molecular-mechanisms-of-resistance-to-first-and-second-generation-alk-inhibitors-in-alk-rearranged-lung-cancer
#14
Justin F Gainor, Leila Dardaei, Satoshi Yoda, Luc Friboulet, Ignaty Leshchiner, Ryohei Katayama, Ibiayi Dagogo-Jack, Shirish Gadgeel, Katherine Schultz, Manrose Singh, Emily Chin, Melissa Parks, Dana Lee, Richard H DiCecca, Elizabeth Lockerman, Tiffany Huynh, Jennifer Logan, Lauren L Ritterhouse, Long P Le, Ashok Muniappan, Subba Digumarthy, Colleen Channick, Colleen Keyes, Gad Getz, Dora Dias-Santagata, Rebecca S Heist, Jochen Lennerz, Lecia V Sequist, Cyril H Benes, A John Iafrate, Mari Mino-Kenudson, Jeffrey A Engelman, Alice T Shaw
Advanced, anaplastic lymphoma kinase (ALK)-positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib and alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients progressing on various ALK inhibitors...
October 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27413712/tackling-alk-in-non-small-cell-lung-cancer-the-role-of-novel-inhibitors
#15
REVIEW
Francesco Facchinetti, Marcello Tiseo, Massimo Di Maio, Paolo Graziano, Emilio Bria, Giulio Rossi, Silvia Novello
Crizotinib is an oral inhibitor of anaplastic lymphoma kinase (ALK) with remarkable clinical activity in patients suffering from ALK-rearranged non-small cell lung cancer (NSCLC), accounting to its superiority compared to chemotherapy. Unfortunately, virtually all ALK-rearranged tumors acquire resistance to crizotinib, frequently within one year since the treatment initiation. To date, therapeutic strategies to overcome crizotinib resistance have focused on the use of more potent and structurally different compounds...
June 2016: Translational Lung Cancer Research
https://www.readbyqxmd.com/read/27401797/lorlatinib-is-active-in-drug-resistant-nsclc
#16
(no author information available yet)
Data from a phase I study indicate that the investigational ALK inhibitor lorlatinib is active in patients with ALK- or ROS1-positive non-small cell lung cancer, including those with brain metastases. Objective responses were seen among patients with known ALK resistance mutations who had relapsed following treatment with other tyrosine kinase inhibitors.
August 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27401242/crizotinib-resistant-ros1-mutations-reveal-a-predictive-kinase-inhibitor-sensitivity-model-for-ros1-and-alk-rearranged-lung-cancers
#17
Francesco Facchinetti, Yohann Loriot, Mei-Shiue Kuo, Linda Mahjoubi, Ludovic Lacroix, David Planchard, Benjamin Besse, Françoise Farace, Nathalie Auger, Jordi Remon, Jean-Yves Scoazec, Fabrice André, Jean-Charles Soria, Luc Friboulet
BACKGROUND: The identification of molecular mechanisms conferring resistance to tyrosine kinase inhibitor (TKI) is a key step to improve therapeutic results for patients with oncogene addiction. Several alterations leading to EGFR and anaplastic lymphoma kinase (ALK) resistance to TKI therapy have been described in non-small cell lung cancer (NSCLC). Only two mutations in the ROS1 kinase domain responsible for crizotinib resistance have been described in patients thus far. METHODS: A patient suffering from a metastatic NSCLC harboring an ezrin (EZR)-ROS1 fusion gene developed acquired resistance to the ALK/ROS1 inhibitor crizotinib...
December 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27144863/crizotinib-resensitization-by-compound-mutation
#18
LETTER
Paola Bordi, Marzia Del Re, Marcello Tiseo
No abstract text is available yet for this article.
May 5, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/27144862/crizotinib-resensitization-by-compound-mutation
#19
LETTER
Alice T Shaw, Jeffrey A Engelman
No abstract text is available yet for this article.
May 5, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/26951079/second-and-third-generation-alk-inhibitors-for-non-small-cell-lung-cancer
#20
REVIEW
Jingjing Wu, John Savooji, Delong Liu
Crizotinib as the first-generation ALK inhibitor has shown significant activity in ALK-mutated non-small cell lung cancer (NSCLC). Second- and third-generation ALK inhibitors are entering clinical applications for ALK+ NSCLC. In addition, a third-generation ALK inhibitor, lorlatinib (PF-06463922), was reported to resensitize NSCLC to crizotinib. This review provided a summary of clinical development of alectinib, ceritinib, brigatinib (AP26113), and lorlatinib.
March 8, 2016: Journal of Hematology & Oncology
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