Lorlatinib, a novel generation oral anaplastic lymphoma kinase (ALK) and ROS1 inhibitor with high membrane and blood-brain barrier permeability, recently received accelerated approval for treatment of ALK-rearranged non-small-cell lung cancer (NSCLC), and its further clinical development is ongoing. We previously found that the efflux transporter P-glycoprotein (MDR1/ABCB1) restricts lorlatinib brain accumulation and that the drug-metabolizing enzyme cytochrome P450-3A (CYP3A) limits its oral availability. Using genetically modified mouse models, we investigated the impact of targeted pharmacological inhibitors on lorlatinib pharmacokinetics and bioavailability. Upon oral administration of lorlatinib, the plasma AUC0-8h in CYP3A4-humanized mice was ∼1.8-fold lower than in wild-type and Cyp3a–/– mice. Oral coadministration of the CYP3A inhibitor ritonavir caused reversion to the AUC0-8h levels seen in wild-type and Cyp3a–/– mice, without altering the relative tissue distribution of lorl..... READ ARTICLE
European Journal of Pharmaceutics and Biopharmaceutics
DOI:10.1016/j.ejpb.2019.01.016
Authors: Wenlong Li, Rolf W. Sparidans, Yaogeng Wang, Maria C. Lebre, Jos H. Beijnen, Alfred H. Schinkel
We discovered lorlatinib-resistant multiple ALK-compound mutations and an L1256F single mutation as well as the potential therapeutic strategies for these ALK mutations. Our original computational simulation to calculate the binding affinity may be applicable for predicting resistant mutations and for overcoming drug resistance in silico. READ ARTICLE
EBioScience DOI: 10.1016/j.ebiom.2019.01.019
Authors: Koutaroh Okada, Mitsugu Araki, Takuya Sakashita, Biao Ma, Ryo Kanada, Noriko Yanagitani, Atsushi Horiike, Sumi Koike, Tomoo Oh-hara, Kana Watanabe, Keiichi Tamai, Makoto Maemondo, Makoto Nishio, Takeshi Ishikawa, Yasushi, Okuno, Naoya Fjita, Ryohei Katayama
Read MoreAlectinib continues to demonstrate superior investigator-assessed PFS versus crizotinib in untreated ALK-positive NSCLC, irrespective of EML4-ALK variant. READ HERE
Journal of Thoracic Oncology DOI: 10.1016/j.jtho.2019.03.007
Authors: D. Ross Camidge, Rafal Dziadziuszko, Solange Peters, Tony Mok,Johannes Noe, Malgorzata Nowicka, Shirish M. Gadgeel, Parneet Cheema, MD, Nick Pavlakis, Filippo de Marinis, Byoung Chul Cho, Li Zhang, Denis Moro-Sibilot, Ting Liu, Walter Bordogna, Bogdana Balas, Barbara Müller,Alice T. Shaw
Read MoreTo our knowledge, this is the first detailed case of an anaplastic lymphoma kinase (ALK)-positive patient with central nervous system (CNS) disease who experienced clinical benefit with lorlatinib after disease progression during treatment with high-dose brigatinib.
The efficacy of lorlatinib might reflect activity against an interval change in the biology of ALK-positive CNS disease occurring after initial brigatinib benefit that was not able to be suppressed by brigatinib. READ ARTICLE
Clinical Lung Cancer DOI:10.1016/j.cllc.2018.11.010
Authors: Mandy R. Sakamoto, Justin M. Honce, Deborah L. Lindquist, D. Ross Camidge
Gene fusions involving the anaplastic lymphoma kinase gene (ALK) often leads to oncogenic activation of the ALK kinase resulting in tumor development in lung and other solid tumors. Accurate identification of the fusion gene in patients with lung cancer has profoundly impacted patients’ clinical performance and long-term survival. READ ARTICLE
Clinical Lung Cancer DOI:10.1016/j.cllc.2018.11.002
Authors: Hongzheng Ren, Xiaonan Hou, Patrick W. Eiken, Jin Zhang, Karlyn E. Pierson, Asha A. Nair, Jaime I. Davila, Helena Kovarikova, Jin Sung Jang, Sarah H. Johnson, Julian R. Molina, Randolph S. Marks, Ping Yang, Joanne E. Yi, Aaron S. Mansfield, Jin Jen
ALK-positive (ALK+) lung adenocarcinoma usually shows a more advanced-staged disease with frequent nodal metastasis and highly aggressive outcomes compared with EGFR-mutated lung cancers. The aim of this study was to investigate the expression profiles of several mucins in ALK + lung cancers to gain insight into the relationship between the more aggressive biological nature of ALK + lung cancers and the role of mucins. We examined the immunohistochemical profiles of mucins MUC1, MUC2, MUC5AC, and MUC6 in 19 ALK + lung cancers compared with 42 EGFR-mutated lung cancers. ALK + cancers were found to occur in younger patients and were characterized by a solid-predominant histologic subtype with frequent signet ring cells and peritumoral muciphages. By contrast, EGFR-mutated cancers lacked ALK-specific histological patterns. Although all MUC1 and MUC5AC were expressed in both subtypes, MUC1 expression in ALK + cancers was visualized exclusively through cytoplasmic staining, whereas those in..... READ ARTICLE
Pathology - Research and Practice DOI:10.1016/j.prp.2018.12.011
Authors: Hong Kyu Lee, Mi Jung Kwon, Jinwon Seo, Jeong Won Kim, Mineui Hong, Hye-Rim Park, Soo Kee Min, Ji-Young Choe, Yong Joon Ra, Seung Hun Jang, Yong Il Hwang, Ho Young Kim, Kyueng-Whan Min
A subset of leiomyosarcomas harbor previously unrecognized oncogenic ALK fusions that are highly responsive to ALK inhibitors and thus these data emphasize the importance of detailed genomic investigations of leiomyosarcoma tumors. Overall, these findings suggest that some soft-tissue sarcomas may harbor previously unknown kinase gene translocations, and their discovery may propel new therapeutic strategies in this treatment-refractory cancer. READ ARTICLE
Molecular Cancer Research DOI:10.1158/1541-7786.MCR-18-1075
Authors: Lara E. Davis, Kevin D. Nusser, Joanna Przybyl, Janét Pittsenbarger, Nicolle E. Hofmann, Sushama Varma, Sujay Vennam, Maria Debiec-Rychter, Matt van de Rijn and Monika A. Davare
We present a 76-year-old Japanese male who had a history of removal of a gastric gastrointestinal stromal tumor (GIST) 6 years ago. Although asymptomatic and having no evidence of recurrence, follow-up endoscopy revealed a small, white depressed lesion of approximately 1 cm with converging mucosal folds in the greater curvature of the fundus, which was suspicious of depressed-type early gastric cancer (GC) by conventional endoscopy. However, no evidence of GC except a “white globe appearance”-like area was identified by magnifying endoscopy with blue laser imaging. The biopsy specimens showed a proliferation of anaplastic lymphoma kinase (ALK)-positive spindle cells in the gastric mucosa, and ALK-rearrangement was detected by fluorescent in situ hybridization. Furthermore, clathrin heavy chain (CLTC)-ALK fusion was seen by genetic analysis, thus the lesion was preoperatively diagnosed as gastric inflammatory myofibroblastic tumor (IMT). For the curative intent, a laparoscopic endoscopi..... READ ARTICLE
Human Pathology DOI:10.1016/j.ehpc.2018.12.005
Authors: Mai Nakanishi, Jiro Watari, Toshihiko Tomita, Yasutaka Nakanishi, Yoshitane Tsukamoto, Shohei Matsuo, Takashi Uchihashi, Junichi Miyazaki, Hironori Tanaka, Shoudou Kojima, Nobukazu Kuroda,Ikuo Matsuda, Hiroto Miwa, Hisashi Shinohara, Seiichi Hirota
Mutation profiling using liquid biopsy has become a promising approach for monitoring tumor genomic evolution when tissue biopsy is not available. READ ARTICLE
Clinical Lung Cancer DOI:10.1016/j.cllc.2019.02.014
Authors: MeijuanDing, Lili Deng, Ruoying Yu, Dan Lu, Yun Bai, Xue Wu, Yang W. Shao, Yu Yang
Background: Detection of ALK and ROS1 gene rearrangements in non–small-cell lung cancer is required for directing patient care. Although fluorescence in situ hybridization (FISH) and immunohistochemistry have been established as gold standard methods, next-generation sequencing (NGS) platforms are called to be at least equally successful. Comparison of these methods for translation into daily use is currently under investigation. Conclusion: Our data support that the identification of 3' isolated signal FISH pattern in ALK and ROS1 cases might suggest a false-positive result. NGS seems a reliable technique to assess ALK and ROS1 rearrangements, offering the advantage over immunohistochemistry of detecting other molecular alterations with potential therapeutic implications. READ ARTICLE
Clinical Lung Cancer DOI:10.1016/j.cllc.2019.02.008
Authors: Sergi Clavé, Natalia Rodon, Lara Pijuan, Olga Díaz, Marta Lorenzo, Pedro Rocha, Álvaro Taus, Remei Blanco, Joaquim Bosch-Barrera, Noemí Reguart, Noelia de la Torre, Glòria Oliveras, Blanca Espinet, Beatriz Bellosillo, Xavier Puig, Edurne Arriola, Marta Salido
Introduction: We retrospectively analyzed the effects of crizotinib on serum creatinine and creatinine-based estimated glomerular filtration rate (eGFR) in patients with anaplastic lymphoma kinase–positive advanced NSCLC across four trials (NCT00585195, NCT00932451, NCT00932893, and NCT01154140). Conclusions: Crizotinib resulted in a decline in creatinine-based estimates of renal function mostly over the first 2 weeks of treatment. However, there was minimal evidence of cumulative effects with prolonged treatment and these changes were largely reversible following treatment discontinuation, consistent with previous reports suggesting this may be predominantly an effect on creatinine secretion as opposed to true nephrotoxicity. READ ARTICLE
Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.02.015
Authors: D. Ross Camidge, Elizabeth E. Kim, Tiziana Usari, Anna Polli,Iona Lewis and Keith D. Wilner
Background: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have shown efficacy in the treatment of ALK-rearranged non–small-cell lung cancer (NSCLC), but the disease eventually progresses in all patients. In many cases, resistance to ALK TKIs arises through ALK mutations. Although clinical and biological data suggest variations in TKI efficacy according to the mechanism of resistance, ALK mutations are still rarely investigated in routine practice. Conclusion: Targeted next-generation sequencing is suitable for detecting ALK resistance mutations in ALK-rearranged NSCLC patients in routine practice. It might help select the best treatment at the time of disease progression during treatment with an ALK TKI. READ ARTICLE
Clinical Lung Cancer DOI:10.1016/j.cllc.2019.02.013
Authors: Philippe Jamme, Clotilde Descarpentries, Radj Gervais, Eric Dansin, Marie Wislez, Valérie Grégoire, Nicolas Richard, Simon Baldacci, Nathalie Rabbe, Maeva Kyheng, Zoulika Kherrouche, Fabienne Escande, Marie Christine Copin, Alexis B. Cortot
Concomitant inhibition of anaplastic lymphoma kinase (ALK) and bromodomain-4 (BRD4) is a potential therapeutic strategy for targeting two key oncogenic drivers that co-segregate in a significant fraction of high-risk neuroblastoma patients, mutation of ALK and amplification of MYCN. Starting from known dual polo-like kinase (PLK)-1–BRD4 inhibitor BI-2536, we employed structure-based design to redesign this series toward compounds with a dual ALK–BRD4 profile. These efforts led to compound (R)-2-((2-ethoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)-7-ethyl-5-methyl-8-((4-methylthiophen-2-yl)methyl)-7,8-dihydropteridin-6(5H)-one (16k) demonstrating improved ALK activity and significantly reduced PLK-1 activity, while maintaining BRD4 activity and overall kinome selectivity. We demonstrate the compounds’ on-target engageme READ ARTICLE
Journal of Medicinal Chemistry DOI:10.1021/acs.jmedchem.8b01947
Authors: Ellen Watts, David Heidenreich, Elizabeth Tucker, Monika Raab, Klaus Strebhardt, Louis Chesler, Stefan Knapp, Benjamin Bellenie, and Swen Hoelder
Background: High concordance has been observed between Ventana D5F3 ALK immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH) in lung adenocarcinoma (LADC). However, whether a similar conclusion can be applied to lung squamous-cell carcinoma (LSCC) has remained unclear. We therefore evaluated the ALK (anaplastic lymphoma kinase) status and the therapeutic effect of an ALK tyrosine kinase inhibitor (TKI) in IHC- or FISH-positive LSCC. Conclusions: The positive concordance rate of ALK IHC and FISH in LSCC is far less than that reported for LADC. Therefore, ALK IHC detection in LSCC cannot be used as a diagnostic method for ALK rearrangement. READ ARTICLE
Lung Cancer
DOI:10.1016/j.lungcan.2019.02.015
Authors: Haiyue Wang, Leina Sun,Yaxiong Sang, Xin Yang, Guangming Tian, Ziping Wang, Jian Fang, Wei Sun, Lixin Zhou, Ling Jia, Ming-Sound Tsao, Huaiyin Shi, Dongmei Lin
A circRNA signature was identified as a potential noninvasive biomarker for LUAD diagnosis. This study aimed to evaluate whether circulating circRNAs could be used as diagnostic biomarkers for lung adenocarcinoma (LUAD). READ ARTICLE
Journal of Translational Medicine
DOI:10.1186/s12967-019-1800-z
Authors: Xiao-Xia Liu, Yi-E Yang, Xiao Liu, Meng-Yu Zhang, Rui Li, Yun-Hong Yin, and Yi-Qing Qu
We conducted a large-scale surveillance study as a post–marketing commitment to investigate the safety and effectiveness of alectinib in patients with ALK-positive non–small-cell lung cancer (NSCLC) in Japan. Patients receiving 300 mg twice-daily alectinib (September 2014 to June 2015) were monitored until termination of alectinib or completion of 18 months of treatment at 519 Japanese study sites. The primary endpoint was the incidence of adverse drug reactions (ADR), which are important identified risks for alectinib in Japanese patients. Overall survival (OS), a key secondary endpoint, was assessed according to information on outcome. Overall, 1251 patients were enrolled. The median patient age was 62.0 years; 12.9% of patients were aged ≥75 years. At baseline, 63.0% of patients had received crizotinib and 40.6% had brain metastases. Altogether, 1512 ADR occurred in 654 patients (53.6%), with 164 grade ≥3 ADR in 123 patients (10.1%). Commonly occurring ADR were hepatic disorders (al..... READ ARTICLE
Cancer Science
DOI:10.1111/cas.13977
Authors: Noriyuki Masuda,Yuichiro Ohe,Akihiko Gemma,Masahiko Kusumoto,Ikuyo Yamada,Tadashi Ishii,Nobuyuki Yamamoto
Background: Both genetic and environmental factors contribute to the development of cancer and its mutant spectrum. Lung cancer has familial aggregation. Lung cancer caused by non-tobacco factors has unique pathological and molecular characteristics. The interaction between genetic lung cancer susceptibility and carcinogens from coal burning remains complex and understudied. Conclusion: FLC and exposure to coal combustion have an important impact on the clinicopathological characteristics and gene fusion mode of NSCLC, particularly in cases of higher levels of carcinogens, and genetic susceptibility has a greater impact. Our findings may help evaluate the effect of FLC and coal exposure on the pathogenesis of lung cancer. READ ARTICLE
Thoracic Cancer
DOI:10.1111/1759-7714.12987
Authors: Ying Chen, Guangjian Li, Yujie Lei, Kaiyun Yang, Huatao Niu, Jie Zhao, Rui He, Huanqi Ning, Qiubo Huang, Qinghua Zhou, Yunchao Huang
Heterogeneity in strategies for survival and proliferation among the cells that constitute a tumour is a driving force behind the evolution of resistance to cancer therapy. The rules mapping the tumour’s strategy distribution to the fitness of individual strategies can be represented as an evolutionary game. We develop a game assay to measure effective evolutionary games in co-cultures of non-small cell lung cancer cells that are sensitive and resistant to the anaplastic lymphoma kinase inhibitor alectinib. The games are not only quantitatively different between different environments, but targeted therapy and cancer-associated fibroblasts qualitatively switch the type of game being played by the in vitro population from Leader to Deadlock. This observation provides empirical confirmation of a central theoretical postulate of evolutionary game theory in oncology: we can treat not only the player, but also the game. Although we concentrate on measuring games played by cancer cells, the measurement methodology we develop can be used to advance the study of games in other microscopic systems by providing a quantitative description of non-cell-autonomous effects. READ ARTICLE
Nature Ecology & Evolution DOI: 10.1038/s41559-018-0768-z
Authors: Artem Kaznatcheev, Jeffrey Peacock, David Basanta, Andriy Marusyk, Jacob G. Scott
Read MoreThe ALK receptor tyrosine kinase (ALK) gene encodes a transmembrane protein rearranged in 2–7% of non-small cell lung cancer (NSCLC) cases. This gene has become the second most studied therapeutic target after EGFR due to the implied therapeutic opportunities. While the diagnostic of ALK rearrangements is well established, small molecules targeting ALK are in constant evolution because tumor cells eventually will develop mechanisms of resistance. In this review we describe the biology of the ALK gene, alterations, epidemiology, diagnostic tests as well as strategies of treatment. READ ARTICLE
Critical Reviews in Oncology/Hematology DOI:10.1016/j.critrevonc.2019.02.006
Authors: Gina Rosas, Rossana Ruiz, Jhajaira M. Araujo, Joseph A. Pinto, Luis Mas
Purpose: To investigate the role of radiotherapy (RT) in the management of EGFR- or ALK-mutated metastatic non-small cell lung cancer (NSCLC) treated with TKI. Conclusions: SRT seems to positively affect OS with limited toxicity in selected patients. READ ARTICLE
La radiologia medica
DOI:10.1007/s11547-019-00999-w
Authors: Paolo Borghetti,, Marco Lorenzo Bonù, Rachele Giubbolini, Niccolo’ Giaj Levra, Rosario Mazzola, Marco Perna, Luca Visani, Fiammetta Meacci, Maria Taraborrelli, Luca Triggiani, Davide Franceschini, Carlo Greco, Alessio Bruni, Stefano Maria Magrini, Vieri Scotti