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https://www.readbyqxmd.com/read/27888620/identification-of-different-alk-mutations-in-a-pair-of-neuroblastoma-cell-lines-established-at-diagnosis-and-relapse
#1
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...
November 24, 2016: Oncotarget
https://www.readbyqxmd.com/read/27693947/identification-of-non-resistant-ros-1-inhibitors-using-structure-based-pharmacophore-analysis
#2
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...
September 29, 2016: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/27693505/drug-resistance-in-alk-positivenon-small-cell-lungcancer-patients
#3
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...
September 29, 2016: 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
#4
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...
October 8, 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
#5
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...
September 20, 2016: Oncotarget
https://www.readbyqxmd.com/read/27432227/molecular-mechanisms-of-resistance-to-first-and-second-generation-alk-inhibitors-in-alk-rearranged-lung-cancer
#6
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
#7
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
#8
(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
#9
Francesco Facchinetti, Yohann Loriot, Mei-Shiue Cassin-Kuo, Linda Mahjoubi, Ludovic Lacroix, David Planchard, Benjamin Besse, Nathalie Auger, Françoise Farace, Jordi Remon, Jean-Yves Scoazec, Fabrice Andre, Jean-Charles Soria, Luc Friboulet
BACKGROUND: The identification of molecular mechanisms conferring resistance to Tyrosine Kinase Inhibitor (TKIs) is a key-step to improve therapeutic results for patients with oncogene-addiction. Several alterations leading to Epidermal Growth Factor Receptor (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...
July 11, 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
#10
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
#11
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
#12
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
https://www.readbyqxmd.com/read/26880581/conformational-studies-and-atropisomerism-kinetics-of-the-alk-clinical-candidate-lorlatinib-pf-06463922-and-desmethyl-congeners
#13
Jeff Elleraas, Jason Ewanicki, Ted W Johnson, Neal W Sach, Michael R Collins, Paul F Richardson
Lorlatinib (PF-06463922) is an ALK/ROS1 inhibitor and is in clinical trials for the treatment of ALK positive or ROS1 positive NSCLC (i.e. specific subsets of NSCLC). One of the laboratory objectives for this molecule indicated that it would be desirable to advance a molecule which was CNS penetrant in order to treat brain metastases. From this perspective, a macrocyclic template was attractive for a number of reasons. In particular, this template reduces the number of rotatable bonds, provides the potential to shield polar surface area and reinforces binding through a restricted conformation...
March 7, 2016: Angewandte Chemie
https://www.readbyqxmd.com/read/26801737/resensitizing-refractory-alk-nsclc-a-case-study
#14
(no author information available yet)
A case report shows that drug resistance in ALK-positive non-small cell lung cancer is a dynamic process. In this patient, an acquired mutation conferring resistance to the highly selective investigational ALK inhibitor lorlatinib unexpectedly restored responsiveness to crizotinib, an older and less potent drug.
March 2016: Cancer Discovery
https://www.readbyqxmd.com/read/26698910/resensitization-to-crizotinib-by-the-lorlatinib-alk-resistance-mutation-l1198f
#15
Alice T Shaw, Luc Friboulet, Ignaty Leshchiner, Justin F Gainor, Simon Bergqvist, Alexei Brooun, Benjamin J Burke, Ya-Li Deng, Wei Liu, Leila Dardaei, Rosa L Frias, Kate R Schultz, Jennifer Logan, Leonard P James, Tod Smeal, Sergei Timofeevski, Ryohei Katayama, A John Iafrate, Long Le, Michele McTigue, Gad Getz, Ted W Johnson, Jeffrey A Engelman
In a patient who had metastatic anaplastic lymphoma kinase (ALK)-rearranged lung cancer, resistance to crizotinib developed because of a mutation in the ALK kinase domain. This mutation is predicted to result in a substitution of cysteine by tyrosine at amino acid residue 1156 (C1156Y). Her tumor did not respond to a second-generation ALK inhibitor, but it did respond to lorlatinib (PF-06463922), a third-generation inhibitor. When her tumor relapsed, sequencing of the resistant tumor revealed an ALK L1198F mutation in addition to the C1156Y mutation...
January 7, 2016: New England Journal of Medicine
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