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Chelsea E Powell, Yang Gao, Li Tan, Katherine A Donovan, Radosław P Nowak, Amanda Loehr, Magda Bahcall, Eric S Fischer, Pasi A Jänne, Rani E George, Nathanael S Gray
We present the development of the first small molecule degraders that can induce anaplastic lymphoma kinase (ALK) degradation, including in non-small-cell lung cancer (NSCLC), anaplastic large-cell lymphoma (ALCL), and neuroblastoma (NB) cell lines. These degraders were developed through conjugation of known pyrimidine-based ALK inhibitors, TAE684 or LDK378, and the cereblon ligand pomalidomide. We demonstrate that in some cell types degrader potency is compromised by expression of drug transporter ABCB1. In addition, proteomic profiling demonstrated that these compounds also promote the degradation of additional kinases including PTK2 (FAK), Aurora A, FER, and RPS6KA1 (RSK1)...
May 10, 2018: Journal of Medicinal Chemistry
Libor Stanek, Drahomira Springer, Bohuslav Konopasek, Michal Vocka, Petra Tesarova, Martin Syrucek, Lubos Petruzelka, Ales Vicha, Zdenek Musil
Lung cancer is one of the most common malignant cancers in the Czech Republic in men, with the highest mortality rate of all the malignant diseases. The development of biological treatment enables study into novel personalized treatment options. This type of treatment is usually of high quality, and is often demanding of predictive and biopsy diagnostics, which is dependent on the quality of the collected material and close cooperation among particular departments. The present study describes the complete biopsy and predictive examinations performed in a male patient with lung adenocarcinoma, with an emphasis on the logistics of the whole process and the application of the tyrosine kinase inhibitors, crizotinib and LDK378...
December 2017: Oncology Letters
Nadezda Dolgikh, Simone Fulda
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is often overexpressed in rhabdomyosarcoma (RMS). However, its oncogenic and functional role in RMS remains unclear. Therefore, we investigated the antitumor activity of LDK378 (ceritinib), a new second-generation ALK inhibitor approved for patients with ALK-positive non-small-cell lung cancers. Here, we report that LDK378 reduces cell viability and induces cell death in RMS cell lines at low micromolar IC50 concentrations irrespective of ALK expression levels or phosphorylation status...
November 2017: Anti-cancer Drugs
Jing Zheng, Jianya Zhou, Yanping Zhu, Qian Shen, Jianying Zhou
Pancreatic metastasis from non-small cell lung cancer (NSCLC) is usually asymptomatic or presents with abdominal pain, acute pancreatitis, or jaundice. A lung primary is associated with worse survival compared to pancreatic metastases from other organs. Surgical treatment of solitary metastasis to the pancreas from NSCLC has been reviewed in several studies, one of which had a notable disease-free interval. To our knowledge, there are no prior reports of targeted therapy of pancreatic metastasis of NSCLC followed by a significant response...
April 14, 2017: Oncology Research
Yi Zhao, Yi Yang, Yunhua Xu, Shun Lu, Hong Jian
Most tumors develop resistance to targeted cancer drugs, even though these drugs have produced substantial clinical responses. Here we established anaplastic lymphoma kinase (ALK)-positive drug-resistant lung cancer cell lines, which are resistant to ceritinib (LDK378). We found that ceritinib treatment resulted in robust upregulation of SRC activity, as measured by the phosphorylation of the SRC substrate paxillin. Knockdown of SRC alone with siRNA effectively sensitized ceritinib resistance in ALK-positive cells...
April 2017: FEBS Open Bio
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
Akira Ono, Haruyasu Murakami, Masakuni Serizawa, Kazushige Wakuda, Hirotsugu Kenmotsu, Tateaki Naito, Tetsuhiko Taira, Yasuhiro Koh, Yasuhisa Ohde, Takashi Nakajima, Masahiro Endo, Toshiaki Takahashi
A 57-year-old male current smoker was diagnosed with an aggressive variant of ALK-rearranged inflammatory myofibroblastic tumor (IMT) arising in the pleural cavity. First line treatment with ASP3026 was initiated at a dose of 125mg once daily. A follow-up CT scan revealed drastic regression of the pleural lesion. After disease progression with ASP3026 treatment, LDK378 (ceritinib) was initiated at a dose of 750mg once daily. A follow-up CT scan revealed a second drastic regression of the pleural lesion. Furthermore, it is noteworthy that this case represents the use of serum hyaluronan levels to assist in monitoring of treatment efficacy in an IMT...
September 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
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
Francesco Facchinetti, Caroline Caramella, Nathalie Auger, David Planchard, Julien Adam, Ludovic Lacroix, Jordi Remon, Christophe Massard, Jean-Charles Soria, Luc Friboulet, Benjamin Besse
We report on the case of a patient affected by advanced non-small cell lung cancer (NSCLC) harboring an anaplastic lymphoma kinase (ALK) gene rearrangement who did not respond to crizotinib but subsequently benefited from treatment with ceritinib (LDK378). Although second-generation ALK inhibitors have shown activity in patients pretreated with crizotinib who experienced secondary resistance, this is the first report to date describing their efficacy in a case of primary resistance. Of note, none of the previously described molecular mechanisms explaining resistance to crizotinib was detected on either the initial or post-crizotinib biopsies...
November 11, 2016: Tumori
Raghavendra Achary, Jeong In Yun, Chi Min Park, Gangadhar Rao Mathi, Joo Yun Lee, Jae Du Ha, Chong Hak Chae, Sunjoo Ahn, Chi Hoon Park, Chong Ock Lee, Jong Yeon Hwang, Chang-Soo Yun, Hee Jung Jung, Sung Yun Cho, Hyoung Rae Kim, Pilho Kim
Exploration of the two-position side chain of pyrimidine in LDK378 with tetrahydroisoquinolines (THIQs) led to discovery of 8 and 17 as highly potent ALK inhibitors. THIQs 8 and 17 showed encouraging in vitro and in vivo xenograft efficacies, comparable with those of LDK378. Although THIQ analogs (8a-o and 17a-i) prepared were not as active as their parent compounds, both 8 and 17 have significant inhibitory activities against various ALK mutant enzymes including G1202R, indicating that this series of compounds could be further optimized as useful ALK inhibitors overcoming the resistance issues found from crizotinib and LDK378...
January 15, 2016: Bioorganic & Medicinal Chemistry
D N Debruyne, N Bhatnagar, B Sharma, W Luther, N F Moore, N-K Cheung, N S Gray, R E George
The crizotinib-resistant ALK(F1174L) mutation arises de novo in neuroblastoma (NB) and is acquired in ALK translocation-driven cancers, lending impetus to the development of novel anaplastic lymphoma kinase (ALK) inhibitors with different modes of action. The diaminopyrimidine TAE684 and its derivative ceritinib (LDK378), which are structurally distinct from crizotinib, are active against NB cells expressing ALK(F1174L). Here we demonstrate acquired resistance to TAE684 and LDK378 in ALK(F1174L)-driven human NB cells that is linked to overexpression and activation of the AXL tyrosine kinase and epithelial-to-mesenchymal transition (EMT)...
July 14, 2016: Oncogene
Jing Hu, Xu Zhang, Fang Wang, Xiaokun Wang, Ke Yang, Meng Xu, Kenneth K W To, Qingshan Li, Liwu Fu
Multidrug resistance (MDR) is the leading cause of treatment failure in cancer chemotherapy. The overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1, ABCC1 and ABCG2, play a key role in mediating MDR by pumping anticancer drugs out from cancer cells. Ceritinib (LDK378) is a second-generation tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK) currently in phase III clinical trial for the treatment of non-small cell lung cancer. Here, we found that ceritinib remarkably enhanced the efficacy of chemotherapeutic drugs in ABCB1 or ABCG2 over-expressing cancer cells in vitro and in vivo...
December 29, 2015: Oncotarget
Makoto Nishio, Haruyasu Murakami, Atsushi Horiike, Toshiaki Takahashi, Fumihiko Hirai, Naoko Suenaga, Takeshi Tajima, Kota Tokushige, Masami Ishii, Anthony Boral, Matthew Robson, Takashi Seto
INTRODUCTION: Anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is sensitive to ALK inhibitors, but resistance develops. This study assessed the maximum-tolerated dose, safety, pharmacokinetics (PK), and antitumor activity of ceritinib, a novel ALK inhibitor (ALKi), in Japanese patients with ALK-rearranged malignancies. METHODS: This phase I, multicenter, open-label study (NCT01634763) enrolled adult patients with ALK-rearranged (by fluorescence in situ hybridization and/or immunohistochemistry) locally advanced/metastatic malignancy that had progressed despite standard therapy...
July 2015: Journal of Thoracic Oncology
J Gainor
Anaplastic lymphoma kinase (ALK) gene rearrangements are important therapeutic targets in non-small cell lung cancer (NSCLC) that impart sensitivity to treatment with ALK tyrosine kinase inhibitors (TKIs), such as crizotinib. Indeed, crizotinib is now considered a standard of care for ALK-positive NSCLC patients based upon randomized trials in which crizotinib produced significant improvements in objective response rate (ORR) and progression-free survival (PFS) compared to first- and second-line cytotoxic chemotherapy...
March 2015: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Li Ma, Shucai Zhang
The rate of the anaplastic lymphoma kinase (ALK) gene rearrangements in non-small cell lung cancer (NSCLC) tissues is 3%-5%. The first-in-class ALK tyrosine kinase inhibitor, crizotinib, can effectively target these tumors represent a significant advance in the evolution of personalized medicine for NSCLC. A randomized phase III clinical trial in which superiority of crizotinib over chemotherapy was seen in previously treated ALK-positive NSCLC patients demonstrated durable responses and well tolerance in the majority of ALK-positive NSCLC patients treated with crizotinib...
December 2014: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
Sen Li, Xiaolong Qi, Yufeng Huang, Dingfeng Liu, Fangyu Zhou, Caicun Zhou
The success in identifying the chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) as an oncogenic driver has thoroughly changed the treatment of non-small-cell lung cancer. In the past decade, targeted drugs have emerged as an efficient personalized strategy for ALK-rearranged non-small-cell lung cancer. The accelerated approval of potent ALK inhibitors, such as crizotinib and more recently ceritinib (LDK378), based on the well designed phase I/II trials has been a landmark success in clinical cancer research and contributes a new era of oncogenic targeted therapy characterized by elegant clinical trial design...
March 2015: Clinical Lung Cancer
Tatsushi Kodama, Toshiyuki Tsukaguchi, Yasuko Satoh, Miyuki Yoshida, Yoshiaki Watanabe, Osamu Kondoh, Hiroshi Sakamoto
Alectinib/CH5424802 is a known inhibitor of anaplastic lymphoma kinase (ALK) and is being evaluated in clinical trials for the treatment of ALK fusion-positive non-small cell lung cancer (NSCLC). Recently, some RET and ROS1 fusion genes have been implicated as driver oncogenes in NSCLC and have become molecular targets for antitumor agents. This study aims to explore additional target indications of alectinib by testing its ability to inhibit the activity of kinases other than ALK. We newly verified that alectinib inhibited RET kinase activity and the growth of RET fusion-positive cells by suppressing RET phosphorylation...
December 2014: Molecular Cancer Therapeutics
Kim-Son H Nguyen, Joel W Neal, Heather Wakelee
The last decade has witnessed the development of oncogene-directed targeted therapies that have significantly changed the treatment of non-small-cell lung cancer (NSCLC). In this paper we review the data demonstrating efficacy of gefitinib, erlotinib, and afatinib, which target the epidermal growth factor receptor (EGFR), and crizotinib which targets anaplastic lymphoma kinase (ALK). We discuss the challenge of acquired resistance to these small-molecular tyrosine kinase inhibitors and review promising agents which may overcome resistance, including the EGFR T790M-targeted agents CO-1686 and AZD9291, and the ALK-targeted agents ceritinib (LDK378), AP26113, alectinib (CH/RO5424802), and others...
October 10, 2014: World Journal of Clinical Oncology
Maryann R Cooper, Helen Chim, Hoyi Chan, Cheryl Durand
OBJECTIVE: To review ceritinib for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small-cell lung cancer (NSCLC). DATA SOURCES: Literature searches were conducted in PubMed, EMBASE (1974 to July week 5, 2014), and Google Scholar using the terms ceritinib, LDK378, and non-small-cell lung cancer. STUDY SELECTION AND DATA EXTRACTION: One phase 1 trial and 2 abstracts were identified. DATA SYNTHESIS: Ceritinib is approved for the treatment of ALK-positive metastatic NSCLC in patients who are intolerant to or have progressed despite therapy with crizotinib...
January 2015: Annals of Pharmacotherapy
Jennifer Arrondeau, Samy Ammari, Benjamin Besse, Jean-Charles Soria
No abstract text is available yet for this article.
August 2014: Journal of Thoracic Oncology
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