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https://www.readbyqxmd.com/read/29782561/lorlatinib-in-alk-and-ros1-positive-nsclc-the-future-has-a-start
#1
EDITORIAL
Francesco Facchinetti, Luc Friboulet
No abstract text is available yet for this article.
April 2018: Translational Lung Cancer Research
https://www.readbyqxmd.com/read/29748016/lorlatinib-induced-pulmonary-arterial-hypertension
#2
Alexandre Chabrol, Marie Mayenga, Abdul Momen Hamid, Sylvie Friard, Hélène Salvator, Hélèe Doubre, Séverine Fraboulet, Anne-Cécile Metivier, Emilie Catherinot, Elisabeth Rivaud, Marie Camille Chaumais, David Montani, Louis Jean Couderc, Colas Tcherakian
We report here the first cases, to our knowledge, of pulmonary arterial hypertension induced by lorlatinib. It s the first time that a tyrosine kinase inhibitor for lung cancer is associated with pulmonary arteriel hypertension.
June 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/29744867/p-glycoprotein-mdr1-abcb1-restricts-brain-accumulation-and-cytochrome-p450-3a-cyp3a-limits-oral-availability-of-the-novel-alk-ros1-inhibitor-lorlatinib
#3
Wenlong Li, Rolf W Sparidans, Yaogeng Wang, Maria C Lebre, Els Wagenaar, Jos H Beijnen, Alfred H Schinkel
Lorlatinib (PF-06463922) is a promising oral anaplastic lymphoma kinase (ALK) and ROS1 inhibitor currently in Phase III clinical trials for treatment of non-small cell lung cancer (NSCLC) containing an ALK rearrangement. With therapy-resistant brain metastases a major concern in NSCLC, lorlatinib was designed to have high membrane and blood-brain barrier permeability. We investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, and the multispecific drug-metabolizing enzyme CYP3A in plasma pharmacokinetics and tissue distribution of lorlatinib using genetically modified mouse strains...
May 9, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29738763/3d-culture-system-containing-gellan-gum-restores-oncogene-dependence-in-ros1-rearrangements-non-small-cell-lung-cancer
#4
Bo Gong, Tomoko Oh-Hara, Naoya Fujita, Ryohei Katayama
The ROS1 fusion gene has been identified in approximately 1% of non-small cell lung cancer (NSCLC) cases. Several clinical studies have highlighted ROS1 as a promising therapeutic target because crizotinib, a multi-targeted drug against ROS1, ALK, and the MET proto-oncogene, has elicited remarkable responses in ROS1-rearrangements NSCLC. However, acquired resistance mediated by ROS1 kinase domain mutations has been identified and a system to assess ROS1 inhibitors for these resistant mutations is necessary for the promotion of drug development...
May 5, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29723525/alk-is-required-for-nlrp3-inflammasome-activation-in-macrophages
#5
Bibo Zhang, Wei Wei, Jiaming Qiu
The NLRP3 inflammasome is a key mediator of host immune responses through the induction of pyroptosis and the release of cytokines. Although the pathologic role of inflammasome in infection and sterile inflammation is well known, the mechanism and regulation of NLRP3 inflammasome activation remains obscure. Here, we report that anaplastic lymphoma kinase (ALK) is a novel regulator of NLRP3 inflammasome activation in macrophages. Pharmacologic or genetic inhibition of ALK through targeted drugs (ceritinib and lorlatinib) or RNAi blocked extracellular ATP-induced NLRP3 inflammasome activation in macrophages...
April 30, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29650534/sequential-alk-inhibitors-can-select-for-lorlatinib-resistant-compound-alk-mutations-in-alk-positive-lung-cancer
#6
Satoshi Yoda, Jessica J Lin, Michael S Lawrence, Benjamin J Burke, Luc Friboulet, Adam Langenbucher, Leila Dardaei, Kylie Prutisto-Chang, Ibiayi Dagogo-Jack, Sergei Timofeevski, Harper Hubbeling, Justin F Gainor, Lorin A Ferris, Amanda K Riley, Krystina E Kattermann, Daria Timonina, Rebecca S Heist, A John Iafrate, Cyril H Benes, Jochen K Lennerz, Mari Mino-Kenudson, Jeffrey A Engelman, Ted W Johnson, Aaron N Hata, Alice T Shaw
The cornerstone of treatment for advanced ALK-positive lung cancer is sequential therapy with increasingly potent and selective ALK inhibitors. The third-generation ALK inhibitor lorlatinib has demonstrated clinical activity in patients who failed previous ALK inhibitors. To define the spectrum of ALK mutations that confer lorlatinib resistance, we performed accelerated mutagenesis screening of Ba/F3 cells expressing EML4-ALK. Under comparable conditions, ENU mutagenesis generated numerous crizotinib-resistant but no lorlatinib-resistant clones harboring single ALK mutations...
April 12, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29550682/bioanalytical-assay-for-the-quantification-of-the-alk-inhibitor-lorlatinib-in-mouse-plasma-using-liquid-chromatography-tandem-mass-spectrometry
#7
Claudia Spatari, Wenlong Li, Alfred H Schinkel, Gaetano Ragno, Jan H M Schellens, Jos H Beijnen, Rolf W Sparidans
A bio-analytical assay for the first third generation ALK inhibitor lorlatinib in mouse plasma was developed and validated. Ten-μl plasma samples were prepared by adding rucaparib as the internal standard and precipitation of the plasma proteins. For LC-MS/MS analysis, compounds were eluted at 0.5 mL/min and separated on a 3-μm particle-size, polar embedded octadecyl silica column by gradient elution using 0.1% of formic acid (in water) and methanol. Compounds were monitored with positive electrospray ionization using a triple quadrupole mass spectrometer in selected reaction monitoring mode...
April 15, 2018: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/29505033/shp2-inhibition-restores-sensitivity-in-alk-rearranged-non-small-cell-lung-cancer-resistant-to-alk-inhibitors
#8
Leila Dardaei, Hui Qin Wang, Manrose Singh, Paul Fordjour, Katherine X Shaw, Satoshi Yoda, Grainne Kerr, Kristine Yu, Jinsheng Liang, Yichen Cao, Yan Chen, Michael S Lawrence, Adam Langenbucher, Justin F Gainor, Luc Friboulet, Ibiayi Dagogo-Jack, David T Myers, Emma Labrot, David Ruddy, Melissa Parks, Dana Lee, Richard H DiCecca, Susan Moody, Huaixiang Hao, Morvarid Mohseni, Matthew LaMarche, Juliet Williams, Keith Hoffmaster, Giordano Caponigro, Alice T Shaw, Aaron N Hata, Cyril H Benes, Fang Li, Jeffrey A Engelman
Most anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung tumors initially respond to small-molecule ALK inhibitors, but drug resistance often develops. Of tumors that develop resistance to highly potent second-generation ALK inhibitors, approximately half harbor resistance mutations in ALK, while the other half have other mechanisms underlying resistance. Members of the latter group often have activation of at least one of several different tyrosine kinases driving resistance. Such tumors are not expected to respond to lorlatinib-a third-generation inhibitor targeting ALK that is able to overcome all clinically identified resistant mutations in ALK-and further therapeutic options are limited...
May 2018: Nature Medicine
https://www.readbyqxmd.com/read/29458783/precision-medicine-in-alk-rearranged-nsclc-a-rapidly-evolving-scenario
#9
REVIEW
Alfredo Addeo, Fabrizio Tabbò, Tim Robinson, Lucio Buffoni, Silvia Novello
IMPORTANCE: The identification of anaplastic lymphoma kinase (ALK) rearrangements in 2-5% of non-small cell lung cancer (NSCLC) patients led to the rapid clinical development of its oral tyrosine kinase inhibitor (TKI). Crizotinib was the first ALK inhibitor approved and utilised in the treatment of ALK+ NSCLC patients in the second line setting first and subsequently in the first line one. Since then many other ALK inhibitors have been developed (ceritinib, alectinib, brigatinib, lorlatinib,etc) and the treatment paradigm of these patients has considerably drifted...
February 2018: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/29400604/capture-based-ultra-deep-sequencing-in-plasma-ctdna-reveals-the-resistance-mechanism-of-alk-inhibitors-in-a-patient-with-advanced-alk-positive-nsclc
#10
Jing Guo, Lihong Guo, Li Sun, Zhenzhen Wu, Junyi Ye, Jing Liu, Qiang Zuo
BACKGROUND: Anaplastic lymphoma kinase (ALK) is a validated molecular target in non-small-cell lung cancer (NSCLC). However, the clinical benefits of ALK inhibitors are almost universally limited by the emergence of drug resistance. METHODS: We monitored the plasma circulating tumor DNA (ctDNA) using captured-based ultra-deep sequencing analysis of one patient with metastatic ALK-positive NSCLC who had received therapies including first-, second- and third-generation ALK inhibitors...
May 4, 2018: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/29376144/tracking-the-evolution-of-resistance-to-alk-tyrosine-kinase-inhibitors-through-longitudinal-analysis-of-circulating-tumor-dna
#11
Ibiayi Dagogo-Jack, A Rose Brannon, Lorin A Ferris, Catarina D Campbell, Jessica J Lin, Katherine R Schultz, Jennifer Ackil, Sara Stevens, Leila Dardaei, Satoshi Yoda, Harper Hubbeling, Subba R Digumarthy, Markus Riester, Aaron N Hata, Lecia V Sequist, Inga T Lennes, A John Iafrate, Rebecca S Heist, Christopher G Azzoli, Anna F Farago, Jeffrey A Engelman, Jochen K Lennerz, Cyril H Benes, Rebecca J Leary, Alice T Shaw, Justin F Gainor
Purpose: ALK rearrangements predict for sensitivity to ALK tyrosine kinase inhibitors (TKIs). However, responses to ALK TKIs are generally short-lived. Serial molecular analysis is an informative strategy for identifying genetic mediators of resistance. Although multiple studies support the clinical benefits of repeat tissue sampling, the clinical utility of longitudinal circulating tumor DNA analysis has not been established in ALK-positive lung cancer. Methods: Using a 566-gene hybrid-capture next-generation sequencing (NGS) assay, we performed longitudinal analysis of plasma specimens from 22 ALK-positive patients with acquired resistance to ALK TKIs to track the evolution of resistance during treatment...
2018: JCO Precision Oncology
https://www.readbyqxmd.com/read/29373100/impact-of-eml4-alk-variant-on-resistance-mechanisms-and-clinical-outcomes-in-alk-positive-lung-cancer
#12
Jessica J Lin, Viola W Zhu, Satoshi Yoda, Beow Y Yeap, Alexa B Schrock, Ibiayi Dagogo-Jack, Nicholas A Jessop, Ginger Y Jiang, Long P Le, Kyle Gowen, Philip J Stephens, Jeffrey S Ross, Siraj M Ali, Vincent A Miller, Melissa L Johnson, Christine M Lovly, Aaron N Hata, Justin F Gainor, Anthony J Iafrate, Alice T Shaw, Sai-Hong Ignatius Ou
Purpose Advanced anaplastic lymphoma kinase ( ALK) fusion-positive non-small-cell lung cancers (NSCLCs) are effectively treated with ALK tyrosine kinase inhibitors (TKIs). However, clinical outcomes in these patients vary, and the benefit of TKIs is limited as a result of acquired resistance. Emerging data suggest that the ALK fusion variant may affect clinical outcome, but the molecular basis for this association is unknown. Patients and Methods We identified 129 patients with ALK-positive NSCLC with known ALK variants...
April 20, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29361925/long-term-progression-free-survival-in-an-advanced-lung-adenocarcinoma-patient-harboring-ezr-ros1-rearrangement-a-case-report
#13
Liang Dong, Jingwen Xia, Jing Zhang, Yuanyuan Zhang, Ning Zhu, Peng Zhang, Youzhi Zhang, Xiujuan Zhang, Shengqing Li
BACKGROUND: Crizotinib is recommended as first-line therapy in ROS1-driven lung adenocarcinoma. However, the optimal first-line therapy for this subgroup of lung cancer is controversial according to the available clinical data. CASE PRESENTATION: Here, we describe a 57-year-old man who was diagnosed with stage IIIB lung adenocarcinoma and EGFR/KRAS/ALK-negative tumors. The patient received six cycles of pemetrexed plus cisplatin as first-line therapy and then pemetrexed as maintenance treatment, with a progression-free survival (PFS) of 42 months...
January 23, 2018: BMC Pulmonary Medicine
https://www.readbyqxmd.com/read/29242590/lung-cancer-first-in-man-phase-i-trial-with-lorlatinib
#14
Diana Romero
No abstract text is available yet for this article.
January 2018: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/29174221/lung-toxicity-in-non-small-cell-lung-cancer-patients-exposed-to-alk-inhibitors-report-of-a-peculiar-case-and-systematic-review-of-the-literature
#15
REVIEW
Benedetta Pellegrino, Francesco Facchinetti, Paola Bordi, Mario Silva, Letizia Gnetti, Marcello Tiseo
Lung toxicity is a potential fatal effect involving non-small-cell lung cancer (NSCLC) patients exposed to tyrosine kinase inhibitors (TKIs). Moving from our experience regarding a patient who developed lung toxicity while receiving 2 different anaplastic lymphoma kinase (ALK)-TKIs, we performed a systematic review to assess the epidemiologic magnitude and the clinical significance of such toxicity in NSCLC patients treated with ALK-TKIs. Studies were identified using MEDLINE and additional sources (European Society for Medical Oncology, American Society of Clinical Oncology, and World Conference on Lung Cancer abstracts) in agreement with Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane guidelines...
March 2018: Clinical Lung Cancer
https://www.readbyqxmd.com/read/29101161/lorlatinib-is-well-tolerated-and-has-activity-in-alk-and-ros1-nsclc
#16
(no author information available yet)
Lorlatinib achieved systemic and intracranial responses in patients with ALK- and ROS1-positive NSCLC.
November 3, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29101158/lorlatinib-in-nsclc-robust-efficacy-seen
#17
(no author information available yet)
The investigational ALK inhibitor lorlatinib, whose early clinical activity was first reported last year, continues to look promising in advanced ALK-positive or ROS1-positive non-small cell lung cancer. In a phase II study, robust responses were seen in previously untreated patients, as well as those who had received as many as three prior ALK inhibitors.
December 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29074098/lorlatinib-in-non-small-cell-lung-cancer-with-alk-or-ros1-rearrangement-an-international-multicentre-open-label-single-arm-first-in-man-phase-1-trial
#18
MULTICENTER STUDY
Alice T Shaw, Enriqueta Felip, Todd M Bauer, Benjamin Besse, Alejandro Navarro, Sophie Postel-Vinay, Justin F Gainor, Melissa Johnson, Jorg Dietrich, Leonard P James, Jill S Clancy, Joseph Chen, Jean-François Martini, Antonello Abbattista, Benjamin J Solomon
BACKGROUND: Most patients with anaplastic lymphoma kinase (ALK)-rearranged or ROS proto-oncogene 1 (ROS1)-rearranged non-small-cell lung cancer (NSCLC) are sensitive to tyrosine kinase inhibitor (TKI) therapy, but resistance invariably develops, commonly within the CNS. This study aimed to analyse the safety, efficacy, and pharmacokinetic properties of lorlatinib, a novel, highly potent, selective, and brain-penetrant ALK and ROS1 TKI with preclinical activity against most known resistance mutations, in patients with advanced ALK-positive or ROS1-positive NSCLC...
December 2017: Lancet Oncology
https://www.readbyqxmd.com/read/29067878/brain-penetration-of-the-ros1-alk-inhibitor-lorlatinib-confirmed-by-pet
#19
T Lee Collier, Kevin P Maresca, Marc D Normandin, Paul Richardson, Timothy J McCarthy, Steven H Liang, Rikki N Waterhouse, Neil Vasdev
The Massachusetts General Hospital Radiochemistry Program, in collaboration with Pfizer, has developed unique11 C and18 F-labeling strategies to synthesize isotopologs of lorlatinib (PF-06463922) which is undergoing phase III clinical trial investigations for treatment of non-small-cell lung cancers with specific molecular alterations. A major goal in cancer therapeutics is to measure the concentrations of this drug in the brain metastases of patients with lung cancer, and penetration of the blood-brain barrier is important for optimal therapeutic outcomes...
January 2017: Molecular Imaging
https://www.readbyqxmd.com/read/29048652/activation-of-src-signaling-mediates-acquired-resistance-to-alk-inhibition-in-lung-cancer
#20
Ryohei Yoshida, Takaaki Sasaki, Yoshinori Minami, Yukiko Hibino, Shunsuke Okumura, Masatoshi Sado, Naoyuki Miyokawa, Satoshi Hayashi, Masahiro Kitada, Yoshinobu Ohsaki
Anaplastic lymphoma kinase (ALK) fusion oncogenes occur in approximately 3-5% of non-small cell lung cancer (NSCLC) cases. Various ALK inhibitors are in clinical use for the treatment of ALK-NSCLC, including the first generation ALK inhibitor, crizotinib, and recently the more highly potent alectinib and ceritinib. However, most tumors eventually become resistant to ALK specific inhibitors. To address the mechanisms underlying the development of ALK inhibitor resistance, we used iTRAQ quantitative mass spectrometry and phosphor-receptor tyrosine kinase arrays to investigate intracellular signaling alterations in ALK inhibitor resistant NSCLC cell lines...
September 28, 2017: International Journal of Oncology
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