DOCSLIB.ORG

The New-Generation Selective ROS1/NTRK Inhibitor DS-6051B Overcomes Crizotinib Resistant ROS1- G2032R Mutation in Preclinical Models

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The New-Generation Selective ROS1/NTRK Inhibitor DS-6051B Overcomes Crizotinib Resistant ROS1- G2032R Mutation in Preclinical Models ARTICLE https://doi.org/10.1038/s41467-019-11496-z OPEN The new-generation selective ROS1/NTRK inhibitor DS-6051b overcomes crizotinib resistant ROS1- G2032R mutation in preclinical models Ryohei Katayama 1, Bo Gong1,2, Noriko Togashi 3, Masaya Miyamoto3, Masaki Kiga3, Shiho Iwasaki3, Yasuki Kamai3, Yuichi Tominaga3, Yasuyuki Takeda3, Yoshiko Kagoshima3, Yuki Shimizu1,2, Yosuke Seto1, Tomoko Oh-hara1, Sumie Koike1, Naoki Nakao4, Hiroyuki Hanzawa4, Kengo Watanabe 3, Satoshi Yoda 5,6, Noriko Yanagitani7, Aaron N. Hata5,6, Alice T. Shaw5,6, Makoto Nishio7, Naoya Fujita1,2 & Takeshi Isoyama 3 1234567890():,; ROS1 gene rearrangement was observed in around 1–2 % of NSCLC patients and in several other cancers such as cholangiocarcinoma, glioblastoma, or colorectal cancer. Crizotinib, an ALK/ROS1/MET inhibitor, is highly effective against ROS1-rearranged lung cancer and is used in clinic. However, crizotinib resistance is an emerging issue, and several resistance mechanisms, such as secondary kinase-domain mutations (e.g., ROS1-G2032R) have been identified in crizotinib-refractory patients. Here we characterize a new selective ROS1/NTRK inhibitor, DS-6051b, in preclinical models of ROS1- or NTRK-rearranged cancers. DS-6051b induces dramatic growth inhibition of both wild type and G2032R mutant ROS1–rearranged cancers or NTRK-rearranged cancers in vitro and in vivo. Here we report that DS-6051b is effective in treating ROS1- or NTRK-rearranged cancer in preclinical models, including crizotinib-resistant ROS1 positive cancer with secondary kinase domain mutations especially G2032R mutation which is highly resistant to crizotinib as well as lorlatinib and entrectinib, next generation ROS1 inhibitors. 1 Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan. 2 Department of Medical Genome Science, Graduate School of Frontier Science, The University of Tokyo, Tokyo 108-8639, Japan. 3 Daiichi Sankyo Co., Ltd, Tokyo 140-8710, Japan. 4 Daiichi Sankyo RD Novare Co., Ltd, Tokyo 134-8630, Japan. 5 Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA. 6 Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. 7 Department of Thoracic Medical Oncology, the Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan. Correspondence and requests for materials should be addressed to R.K. (email: ryohei. [email protected]) or to T.I. (email: [email protected]) NATURE COMMUNICATIONS | (2019) 10:3604 | https://doi.org/10.1038/s41467-019-11496-z | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-11496-z everal genetic alterations that aberrantly activate tyrosine Results Skinases have been identified as oncogenic drivers in non- DS-6051b Inhibits ROS1 Kinase in nanomolar concentrations. small cell lung cancer (NSCLC), and many tyrosine To obtain a potent and selective ROS1 inhibitor, high-throughput kinase inhibitors (TKIs) have been developed to target these inhibitor screening against ROS1 kinase was performed, and driver oncogene products1–5. Among the driver oncogenes, several hit compounds were identified. After robust chemical chromosomal rearrangements of anaplastic lymphoma kinase derivatization and characterization, we found a lead compound (ALK), ROS proto-oncogene 1 (ROS1),rearrangedduring that had inhibitory activities against ROS1 and NTRKs, and lead transfection (RET), and neurotrophic receptor tyrosine kinases optimization finally identified DS-6051b (Fig. 1a). DS-6051b (NTRKs) are each observed in 0.1–5% of NSCLC patients1,2,5,6. potently inhibited recombinant ROS1, NTRK1, and NTRK3 in ROS1 gene rearrangements are observed in ~1–2% of NSCLC sub-nanomolar concentration in an ATP-competitive manner patients and in cholangiocarcinoma, glioblastoma, ovarian, (Fig. 1b). Besides ROS1 and NTRKs, DS-6051b almost completely gastric, and colorectal cancers7.TheROS1oncogenicfusion inhibited ACK, ALK, DDR1, and LTK at 0.2 μM among 160 protein can be targeted by the ALK/ROS1/MET TKI crizoti- kinases in the presence of 1 mM ATP, but did not inhibit other nib8,9, which is approved for the treatment of metastatic 152 kinases strongly (Fig. 1c; Supplementary Fig 1a and Supple- ROS1-rearranged NSCLC. In a phase 1/2 clinical trial mentary Table 1a). In addition, DS-6051b inhibited NTRK2 with (PROFILE 1001), the overall response rate to crizotinib a few nanomolar IC50 values at approximately Km value for ATP, was 72%, and median progression-free survival reached and 40 nM of DS-6051b potently inhibited several other kinases, 19.2 months10. such as NuaK1, JAK2, and MUSK, at approximately Km value of In most cases of ROS1-rearranged NSCLC, crizotinib each kinase for ATP (Supplementary Table 1b). DS-6051b induces marked tumor shrinkage. However, the majority of inhibited the growth of the CD74-ROS1 overexpressed Ba/F3 patients will develop resistance to crizotinib within a few years cells and the ROS1 fusion-positive HCC78 cancer cell line with a of treatment. Several secondary mutations in the ROS1 tyr- lower IC50 than crizotinib (Fig. 1d, e). Consistent with the cell osine kinase domain have been identified from the molecular viability assay data, DS-6051b potently inhibited autopho- analysis of crizotinib-refractory ROS1-rearranged NSCLC sphorylation of ROS1 in CD74-ROS1–expressed Ba/F3 cells and cancer patient samples11,12. The ROS1 G2032R mutation is the SLC34A2-ROS1 harboring HCC78 cells at approximately analogous to the ALK G1202R mutation identified in crizoti- single-digit to double-digit nanomolar concentration (Fig. 1f, g). nib-, ceritinib-, and alectinib-resistant ALK-rearranged lung cancers. ROS1 G2032R is also analogous to the G595R muta- Antitumor activity of DS-6051b in ROS1-rearranged PDC tion in NTRK1 identified in entrectinib-resistant NTRK1- models. For further evaluation of DS-6051b efficacy, we estab- rearranged cancer. lished several ROS1-rearranged cancer cell lines from ROS1 We previously reported that the ALK G1202R mutation con- fusion-positive lung cancer patients and tested the efficacy. Since fers high-level resistance to first- and second-generation ALK no CD74-ROS1 rearrangement-harboring cancer cell line was inhibitors examined13, but is sensitive to the third-generation publicly available, two CD74-ROS1 and one EZR-ROS1- ALK/ROS1 inhibitor lorlatinib (PF-06463922)14. Lorlatinib has rearranged cancer cells were established from the pleural effu- been reported to inhibit ROS1 G2032R, but its half-maximal sions of three TKI-naive patients (JFCR-165, JFCR-168, and inhibitory concentration (IC ) is much higher with ROS1 50 MGH-193-1). These patient-derived cells were sensitive to DS- G2032R compared with ALK G1202R15. We previously found 6051b, crizotinib, lorlatinib, cabozantinib, ceritinib, brigatinib, or that cabozantinib, a clinically approved multi-kinase inhibitor for entrectinib. Lorlatinib has the lowest, and DS-6051b the second thyroid and kidney cancers, is active against ROS1 G2032R lowest IC among the inhibitors tested (Fig. 2a–c). Consistent in vitro, but yet to be evaluated in vivo or in clinical setting16.As 50 with the cell viability assay data, DS-6051b, crizotinib, lorlatinib, ROS1 G2032R is the most common mechanism of resistance to ceritinib, cabozantinib, or foretinib potently inhibited autopho- crizotinib in ROS1-rearranged NSCLC11, the identification of sphorylation of ROS1 in JFCR-165, JFCR-168, and MGH193-1B therapeutic strategies to overcome ROS1 G2032R is critically cells (Fig. 2d–f). Next, we used a glioblastoma U-118 MG cell line, important. harboring the FIG-ROS1 fusion gene, and DS-6051b treatment The NTRK gene family consists of NTRK1, NTRK2, and dose dependently inhibited autophosphorylation of ROS1 in U- NTRK3. It encodes a receptor tyrosine kinase, and plays an 118-MG cells in vitro (Fig. 2g). For in vivo experiments, DS- important role in the nervous system in a ligand-dependent 6051b treatment effectively inhibited tumor growth at ≥25 mg/kg manner. However, in cancer, NTRK is often observed as a fusion DS-6051b without significant body weight loss (Fig. 2h; Supple- oncogene, such as TPM3-NTRK1, which induces constitutive mentary Fig. 5a). In addition, we evaluated the efficacy of DS- activation of NTRK1 tyrosine kinase resulting in cancer pro- 6051b using lung cancer PDX model harboring CD74-ROS1 gression. Since the growth of NTRK fusion-positive cancers fusion gene in vivo, and DS-6051b treatment markedly inhibited depends on TRK tyrosine kinase activity, TRK tyrosine kinase tumor growth at ≥10 mg/kg DS-6051b without significant body inhibitors induce a marked tumor growth inhibition17. Indeed, weight loss (Fig. 2i; Supplementary Fig. 5b). several TRK inhibitors, such as entrectinib or larotrectinib, have demonstrated remarkable responses in NTRK-rearranged cancers across various cancer types, including lung, colorectal, thyroid, DS-6051b potently inhibits NTRK-rearranged cancer in vivo. and pediatric cancers18,19. KM12 colorectal cancer cells are known to harbor the TPM3- Here, we develop and characterize a novel ROS1/NTRK inhi- NTRK1 fusion gene, and are addicted to TPM3-NTRK1-mediated bitor, DS-6051b, which is a potent and selective ROS1 and TRK growth signaling. In our previous study, we developed Ba/F3 cells family inhibitor capable of inhibiting ROS1 G2032R and other expressing TPM3-NTRK1 and identified multiple NTRK1 crizotinib-resistant ROS1 mutants. We investigate the preclinical inhibitor-resistance
Load more

Recommended publications
  • SRC Antibody - N-Terminal Region (ARP32476 P050) Data Sheet
    SRC antibody - N-terminal region (ARP32476_P050) Data Sheet Product Number ARP32476_P050 Product Name SRC antibody - N-terminal region (ARP32476_P050) Size 50ug Gene Symbol SRC Alias Symbols ASV; SRC1; c-SRC; p60-Src Nucleotide Accession# NM_005417 Protein Size (# AA) 536 amino acids Molecular Weight 60kDa Product Format Lyophilized powder NCBI Gene Id 6714 Host Rabbit Clonality Polyclonal Official Gene Full Name V-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) Gene Family SH2D This is a rabbit polyclonal antibody against SRC. It was validated on Western Blot by Aviva Systems Biology. At Aviva Systems Biology we manufacture rabbit polyclonal antibodies on a large scale (200-1000 Description products/month) of high throughput manner. Our antibodies are peptide based and protein family oriented. We usually provide antibodies covering each member of a whole protein family of your interest. We also use our best efforts to provide you antibodies recognize various epitopes of a target protein. For availability of antibody needed for your experiment, please inquire (). Peptide Sequence Synthetic peptide located within the following region: QTPSKPASADGHRGPSAAFAPAAAEPKLFGGFNSSDTVTSPQRAGPLAGG This gene is highly similar to the v-src gene of Rous sarcoma virus. This proto-oncogene may play a role in the Description of Target regulation of embryonic development and cell growth. SRC protein is a tyrosine-protein kinase whose activity can be inhibited by phosphorylation by c-SRC kinase. Mutations in this gene could be involved in the
    [Show full text]
  • Gene Symbol Gene Description ACVR1B Activin a Receptor, Type IB
    Table S1. Kinase clones included in human kinase cDNA library for yeast two-hybrid screening Gene Symbol Gene Description ACVR1B activin A receptor, type IB ADCK2 aarF domain containing kinase 2 ADCK4 aarF domain containing kinase 4 AGK multiple substrate lipid kinase;MULK AK1 adenylate kinase 1 AK3 adenylate kinase 3 like 1 AK3L1 adenylate kinase 3 ALDH18A1 aldehyde dehydrogenase 18 family, member A1;ALDH18A1 ALK anaplastic lymphoma kinase (Ki-1) ALPK1 alpha-kinase 1 ALPK2 alpha-kinase 2 AMHR2 anti-Mullerian hormone receptor, type II ARAF v-raf murine sarcoma 3611 viral oncogene homolog 1 ARSG arylsulfatase G;ARSG AURKB aurora kinase B AURKC aurora kinase C BCKDK branched chain alpha-ketoacid dehydrogenase kinase BMPR1A bone morphogenetic protein receptor, type IA BMPR2 bone morphogenetic protein receptor, type II (serine/threonine kinase) BRAF v-raf murine sarcoma viral oncogene homolog B1 BRD3 bromodomain containing 3 BRD4 bromodomain containing 4 BTK Bruton agammaglobulinemia tyrosine kinase BUB1 BUB1 budding uninhibited by benzimidazoles 1 homolog (yeast) BUB1B BUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast) C9orf98 chromosome 9 open reading frame 98;C9orf98 CABC1 chaperone, ABC1 activity of bc1 complex like (S. pombe) CALM1 calmodulin 1 (phosphorylase kinase, delta) CALM2 calmodulin 2 (phosphorylase kinase, delta) CALM3 calmodulin 3 (phosphorylase kinase, delta) CAMK1 calcium/calmodulin-dependent protein kinase I CAMK2A calcium/calmodulin-dependent protein kinase (CaM kinase) II alpha CAMK2B calcium/calmodulin-dependent
    [Show full text]
  • Adaptive Stress Signaling in Targeted Cancer Therapy Resistance
    Oncogene (2015) 34, 5599–5606 © 2015 Macmillan Publishers Limited All rights reserved 0950-9232/15 www.nature.com/onc REVIEW Adaptive stress signaling in targeted cancer therapy resistance E Pazarentzos1,2 and TG Bivona1,2 The identification of specific genetic alterations that drive the initiation and progression of cancer and the development of targeted drugs that act against these driver alterations has revolutionized the treatment of many human cancers. Although substantial progress has been achieved with the use of such targeted cancer therapies, resistance remains a major challenge that limits the overall clinical impact. Hence, despite progress, new strategies are needed to enhance response and eliminate resistance to targeted cancer therapies in order to achieve durable or curative responses in patients. To date, efforts to characterize mechanisms of resistance have primarily focused on molecular events that mediate primary or secondary resistance in patients. Less is known about the initial molecular response and adaptation that may occur in tumor cells early upon exposure to a targeted agent. Although understudied, emerging evidence indicates that the early adaptive changes by which tumor cells respond to the stress of a targeted therapy may be crucial for tumo r cell survival during treatment and the development of resistance. Here we review recent data illuminating the molecular architecture underlying adaptive stress signaling in tumor cells. We highlight how leveraging this knowledge could catalyze novel strategies to minimize
    [Show full text]
  • Review Tec Kinases: a Family with Multiple Roles in Immunity
    Immunity, Vol. 12, 373±382, April, 2000, Copyright 2000 by Cell Press Tec Kinases: A Family Review with Multiple Roles in Immunity Wen-Chin Yang,*³§ Yves Collette,*³ inositol phosphates, but they are thought to be relevant Jacques A. NuneÁ s,*³ and Daniel Olive*² for binding of PtdIns lipids to the same sites. In most *INSERM U119 cases, PH domains bind preferentially to PtdIns (4,5)P2 Universite de la Me diterrane e and inositol (1,4,5) P3 (Ins (1,4,5) P3). However, the Btk 13009 Marseille PH domain binds PtdIns (3,4,5)P3 and Ins (1, 3, 4, 5)P4 France the tightest. PtdIns (3, 4, 5)P3, one of the products of the action of PI3K, is thought to act as a second messen- ger to recruit regulatory proteins to the plasma mem- brane via their PH domains (see below). Many of the Antigen receptors on T, B, and mast cells are multimo- mutations in Btk that lead to XLA are point mutations lecular complexes that are activated by interactions with that cluster at one end of the PH domain and could be external signals. These signals are then transmitted to predicted to impair binding to Ins (3,4,5)P (for review regulate gene expression and posttranscriptional modi- 3 see Satterthwaite et al., 1998a) (Figure 1b). Similarly, fications. Nonreceptor tyrosine kinases (NRTK) are key CBA/N xid mice carry an R28C mutation in the Btk PH players that relay and integrate these signals. NRTK are domain. The recent structure of the PH domain from divided into distinct families defined by a prototypic Btk complexed with Ins (1,3,4,5)P4 provides an explana- member: Src, Tec, Syk, Csk, Fes, Abl, Jak, Fak, Ack, tion for several mutations associated with XLA: mis- Brk, and Srm (Bolen and Brugge, 1997).
    [Show full text]
  • A Novel Mechanism of Crizotinib Resistance in a ROS1+ NSCLC Patient 11 April 2016
    A novel mechanism of crizotinib resistance in a ROS1+ NSCLC patient 11 April 2016 Molecular analysis of a tumor biopsy from a proto- fusion gene in the crizotinib resistant tumor samples oncogene 1 receptor tyrosine kinase positive compared to the pretreatment tumor samples by (ROS1+) patient with acquired crizotinib resistance DNA sequencing or FISH analysis. SNaPshot revealed a novel mutation in the v-kit Hardy analysis of the crizotinib resistant tumor identified a Zuckerman 4 feline sarcoma viral oncogene novel mutation in the KIT gene encoding the amino homolog receptor tyrosine kinase (KIT) that can acid substitution, pD816G. The drug ponatinib, a potentially be targeted by KIT inhibitors. KIT tyrosine kinase inhibitor, demonstrated inhibition of KITD816G kinase activity. Further, in Chromosomal rearrangements of the gene ROS1+ cells expressing KITD816G the addition of encoding ROS1 in approximately 1-2% of non- ponatinib resensitized cells to crizotinib. small cell lung cancers (NSCLC). Treatment of ROS1+ patients with crizotinib, a small-molecule The authors comment that, "Although our results tyrosine kinase inhibitor, often results in durable demonstrate that ponatinib can overcome KIT- tumor regression. However, despite initial mediated resistance in vitro, it remains unknown treatment success patients typically develop whether ponatinib can overcome this or other KIT resistance to crizotinib and disease progression activating mutations in patients. Detection of KIT inevitably ensues. Understanding the mechanism mutations may allow enrollment of patients with of resistance to crizotinib and identifying new ROS1+ cancer (or other oncogenes), onto clinical targets for therapy will help guide patient trials of KIT inhibitors, however it is likely that dual treatment.
    [Show full text]
  • Comparative Efficacy and Safety of Lorlatinib and Alectinib for ALK
    cancers Systematic Review Comparative Efficacy and Safety of Lorlatinib and Alectinib for ALK-Rearrangement Positive Advanced Non-Small Cell Lung Cancer in Asian and Non-Asian Patients: A Systematic Review and Network Meta-Analysis Koichi Ando 1,2,* , Ryo Manabe 1, Yasunari Kishino 1, Sojiro Kusumoto 1, Toshimitsu Yamaoka 3 , Akihiko Tanaka 1, Tohru Ohmori 1,4 and Hironori Sagara 1 1 Division of Respiratory Medicine and Allergology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan; [email protected] (R.M.); [email protected] (Y.K.); [email protected] (S.K.); [email protected] (A.T.); [email protected] (T.O.); [email protected] (H.S.) 2 Division of Internal Medicine, Showa University Dental Hospital Medical Clinic, Senzoku Campus, Showa University, 2-1-1 Kita-senzoku, Ohta-ku, Tokyo 145-8515, Japan 3 Advanced Cancer Translational Research Institute, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan; [email protected] 4 Department of Medicine, Division of Respiratory Medicine, Tokyo Metropolitan Health and Hospitals Corporation, Ebara Hospital, 4-5-10 Higashiyukigaya, Ohta-ku, Tokyo 145-0065, Japan * Correspondence: [email protected]; Tel.: +81-3-3784-8532 Citation: Ando, K.; Manabe, R.; Kishino, Y.; Kusumoto, S.; Yamaoka, Simple Summary: The treatment of anaplastic lymphoma kinase (ALK) rearrangement-positive T.; Tanaka, A.; Ohmori, T.; Sagara, H. (ALK-p) advanced non-small cell lung cancer (NSCLC) remains a challenge.
    [Show full text]
  • Predicting Cardiac Risk of Anti-Cancer Drugs
    PREDICTING CARDIAC RISK OF ANTI-CANCER DRUGS: A ROLE FOR HUMAN INDUCED PLURIPOTENT STEM CELL-DERIVED CARDIOMYOCYTES Andrew Bruening-Wright, Leslie Ellison, James Kramer, Carlos A. Obejero-Paz Charles River, Cleveland 1 ABSTRACT 3 METHODS 1) The Field Potential and Impedance signals Cardiotoxicity is a major complication of many anti-cancer drugs. Acute effects on cardiac ion channels alter cardiac excitability and induce arrhythmias and ultimately heart failure can develop during chronic treatment. Current in vitro strategies for detecting these risks are minimal and often ineffective, particularly for effects that occur over the course of days or weeks. We aimed to validate a human We used the xCELLigence RTCA CardioECR instrument (ACEA Biosciences) to record impedance and extracellular field A B C cell-based assay that is fast, robust, and predictive of both acute and chronic clinical outcomes. Currently marketed chemotherapeutic agents were tested on the CDI-CardioECR system (CDI/Fujifilm- 2 a b ACEA Biosciences). Cardiomyocytes were exposed for eight days to doxorubicin and various tyrosine kinase inhibitors (erlotinib, lapatinib, nilotinib, sunitinib, and crizotinib) at concentrations comparable potentials. iCell cardiomyocytes , from Cellular Dynamics International/FUJIFILM. Spontaneous twitch activity was recorded for to clinical plasma values. Recordings were made at multiple time points each day and data was analyzed using proprietary algorithms written in VSA and Matlab. Drugs with hERG channel block liability two 48 well plates. Analysis was performed using Origin, Matlab and macros written in VBA. The output of the instrument is the (lapatinib, nilotinib, sunitinib and crizotinib) showed a dose dependent delay in repolarization and an increase in dysrhythmic markers.
    [Show full text]
  • RET Gene Fusions in Malignancies of the Thyroid and Other Tissues
    G C A T T A C G G C A T genes Review RET Gene Fusions in Malignancies of the Thyroid and Other Tissues Massimo Santoro 1,*, Marialuisa Moccia 1, Giorgia Federico 1 and Francesca Carlomagno 1,2 1 Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Naples, Italy; [email protected] (M.M.); [email protected] (G.F.); [email protected] (F.C.) 2 Institute of Endocrinology and Experimental Oncology of the CNR, 80131 Naples, Italy * Correspondence: [email protected] Received: 10 March 2020; Accepted: 12 April 2020; Published: 15 April 2020 Abstract: Following the identification of the BCR-ABL1 (Breakpoint Cluster Region-ABelson murine Leukemia) fusion in chronic myelogenous leukemia, gene fusions generating chimeric oncoproteins have been recognized as common genomic structural variations in human malignancies. This is, in particular, a frequent mechanism in the oncogenic conversion of protein kinases. Gene fusion was the first mechanism identified for the oncogenic activation of the receptor tyrosine kinase RET (REarranged during Transfection), initially discovered in papillary thyroid carcinoma (PTC). More recently, the advent of highly sensitive massive parallel (next generation sequencing, NGS) sequencing of tumor DNA or cell-free (cfDNA) circulating tumor DNA, allowed for the detection of RET fusions in many other solid and hematopoietic malignancies. This review summarizes the role of RET fusions in the pathogenesis of human cancer. Keywords: kinase; tyrosine kinase inhibitor; targeted therapy; thyroid cancer 1. The RET Receptor RET (REarranged during Transfection) was initially isolated as a rearranged oncoprotein upon the transfection of a human lymphoma DNA [1].
    [Show full text]
  • Ponatinib Shows Potent Antitumor Activity in Small Cell Carcinoma of the Ovary Hypercalcemic Type (SCCOHT) Through Multikinase Inhibition Jessica D
    Published OnlineFirst February 9, 2018; DOI: 10.1158/1078-0432.CCR-17-1928 Cancer Therapy: Preclinical Clinical Cancer Research Ponatinib Shows Potent Antitumor Activity in Small Cell Carcinoma of the Ovary Hypercalcemic Type (SCCOHT) through Multikinase Inhibition Jessica D. Lang1,William P.D. Hendricks1, Krystal A. Orlando2, Hongwei Yin1, Jeffrey Kiefer1, Pilar Ramos1, Ritin Sharma3, Patrick Pirrotte3, Elizabeth A. Raupach1,3, Chris Sereduk1, Nanyun Tang1, Winnie S. Liang1, Megan Washington1, Salvatore J. Facista1, Victoria L. Zismann1, Emily M. Cousins4, Michael B. Major4, Yemin Wang5, Anthony N. Karnezis5, Aleksandar Sekulic1,6, Ralf Hass7, Barbara C. Vanderhyden8, Praveen Nair9, Bernard E. Weissman2, David G. Huntsman5,10, and Jeffrey M. Trent1 Abstract Purpose: Small cell carcinoma of the ovary, hypercalcemic type three SWI/SNF wild-type ovarian cancer cell lines. We further (SCCOHT) is a rare, aggressive ovarian cancer in young women identified ponatinib as the most effective clinically approved that is universally driven by loss of the SWI/SNF ATPase subunits RTK inhibitor. Reexpression of SMARCA4 was shown to confer SMARCA4 and SMARCA2. A great need exists for effective targeted a 1.7-fold increase in resistance to ponatinib. Subsequent therapies for SCCOHT. proteomic assessment of ponatinib target modulation in Experimental Design: To identify underlying therapeutic vul- SCCOHT cell models confirmed inhibition of nine known nerabilities in SCCOHT, we conducted high-throughput siRNA ponatinib target kinases alongside 77 noncanonical ponatinib and drug screens. Complementary proteomics approaches pro- targets in SCCOHT. Finally, ponatinib delayed tumor dou- filed kinases inhibited by ponatinib. Ponatinib was tested for bling time 4-fold in SCCOHT-1 xenografts while reducing efficacy in two patient-derived xenograft (PDX) models and one final tumor volumes in SCCOHT PDX models by 58.6% and cell-line xenograft model of SCCOHT.
    [Show full text]
  • Kinase Inhibitors: an Introduction
    David Peters Baran Group Meeting Kinase Inhibitors: An Introduction 2/2/19 INTRODUCTION SIGNAL TRANSDUCTION KINASES ARE IMPORTANT IN HUMAN BIOLOGY/DISEASE: The process describing how a signal (chemical/physical) is transmitted through a - Kinases are a superfamily of proteins (5th largest in humans) cell ultimately resulting in a cellular response - 518 genes and 106 pseudogenes - Diverse in size, subunit structure, and cellular location RECEPTOR TRANSDUCERS EFFECTORS - ~260 residues make up their conserved catalytic core - dysregulation of kinases occurs in many diseases (cancer, inflamatory, degenerative, and autoimmune diseases) - signals can originate inside or outside the cell - 244 of the 518 map to disease loci - signals generally passed through a series of steps (signal transduction pathway) often consisting of multiple enzymes and messengers protein O - pathways open possibility for signal aplification (>1x106) kinase ATP + PROTEIN OH ADP + PROTEIN O P O - Extracellular signals transduced by RTKs, GPCR’s, guanlyl cyclases, or ligand-gated Ion channels O - Phosphorylation is the most prominent covalent modification/signal in KINASES INHIBITORS ARE IMPORTANT IN DISEASE THERAPY/RESEARCH: cellular regulation - currently 51 FDA approved small molecule kinase inhibitors - “converter enzymes” (protein kinases and phosphoprotein phosphorlyases) - 4 FDA approved antibody kinase inhibitors are regulated; conserve ATP/maintain desired target protein state - thousands of known inhibitors spanning the kinome - pathway ends by affecting biomolecule
    [Show full text]
  • Novel Targets and Strategies in Glioblastomas
    Novel Targets And Strategies in Glioblastomas Patrick Y. Wen, M.D. Center For Neuro-Oncology Dana Farber/Brigham and Women’s Cancer Center Division of Neuro-Oncology, Department of Neurology Brigham and Women’s Hospital Harvard Medical School DISCLOSURES • RhStResearch Support • Adv isory Boar d – Amgen – Merck – Astra Zeneca – Novartis – Boehringer Ingelheim – Vascular Biogenic – Esai – NeOnc Inc – EliiExelixis • Speaker – Genentech/Roche – Merck – Geron – Genentech/Roche – Medimmune – Merck – NtiNovartis – Sanofi-Aventis – Vascular Biogenics Treatment of High -Grade Gliomas Milest ones in Neuro‐OlOncology AlApprovals Radiotherapy TMZ up front TMZ for for GBM Lomustine relapsed AA Avastin for accelerated recurrent Carmustine Gliadel wafer approval GBM 1970 1980 1990 2000 2010 First US First US Macdonald commercial CT RANO commercial criteria: Brain Tumor Clinical Trial Criteria Levin criteria: MRI MRI + steroids; WHO Pathology Endpoints CT scans ASCO Criteria Workshop Workshop Technology Advances AA=anaplastic astrocytoma; CT=computed tomography; GBM=glioblastoma multiforme; MRI=magnetic resonance imaging; RANO=Response Assessment in Neuro‐Oncology. VEGF: Aflibercept VEGFR: Axitinib, Brivanib, Cabozantinib, Cediranib, Dasatinib, Foretinib, Lenvatinib, Nintedanib, Pazopanib, Pegdinetanib, Sorafenib, Sunitinib, Vandetanib Ang: CVX 060, Trebananib Tie-2: Cabozantinib EGF: ABT-806, Cetuximab, FGFR: Brivanib, Lenvatinib, Nintedanib Nimotuzumab, Panitumumab CXCR4:Plerixafor: Plerixafor HGF: Rilotumumab IL-2: Basiliximab, Daclizumab ECM BLOOD
    [Show full text]
  • Clinical Activity of Ceritinib in ROS1-Rearranged Non-Small Cell Lung Cancer: Bench to Bedside Report LETTER Vivek Subbiaha,1, David S
    LETTER Clinical activity of ceritinib in ROS1-rearranged non-small cell lung cancer: Bench to bedside report LETTER Vivek Subbiaha,1, David S. Honga, and Funda Meric-Bernstama We read with great interest the article by Davare et al. (1) profiling revealed a CD72-ROS1 rearrangement. The on structural insight of ROS1 tyrosine kinase inhibitors. patient was started on crizotinib at 250 mg orally twice Non-small cell lung cancer (NSCLC) is no longer a single daily and exhibited resolution of metastatic disease. disease but a collection of genetically heterogeneous The patient remained disease-free for 13 mo when tumors with different therapeutic options [e.g., aberra- CT-scan showed a relapse with two nodules in the tions in EGFR, BRAF, HER2/Neu, RET, anaplastic lym- right lower lobe. He underwent stereotactic radiation phoma kinase (ALK), and ROS1-rearranged tumors]. therapy. Imaging showed a treatment response but Each of these options has different clinical characteristics new pleural nodules. MRI brain scan showed new in- and therapeutic options with agents that have varying tracranial metastases. After undergoing gamma knife degrees of systemic activity. ROS1 gene rearrange- radiosurgery, the patient was enrolled in an ipilimumab ments define a distinct molecular subgroup of NSCLC. and radiation trial (NCT02239900). His disease pro- ROS1 rearrangement leads to constitutive ROS1 activa- gressed on ipilimumab. The patient was next enrolled tion and activity of crizotinib against ROS1-rearranged on the “Signature Trial,” a modular phase II study to link NSCLC was noted and crizotinib received regulatory targeted therapy to patients with pathway activated tu- approval for the treatment of ROS1 rearranged NSCLC mors; in this study patients whose tumors have aberra- (2).
    [Show full text]