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Gary K Scott, David Chu, Ravneet Kaur, Julia Malato, Daniel E Rothschild, Katya Frazier, Serenella Eppenberger-Castori, Byron Hann, Ben Ho Park, Christopher C Benz
ERα phosphorylation at hinge site S294 (pS294) was recently shown to be essential for ER-dependent gene transcription and mediated by an unknown cyclin-dependent kinase (CDK). This study was undertaken to identify the exact CDK pathway mediating pS294 formation, and to determine if this phosphorylation event occurs with, and can be targeted to treat, the ligand-independent growth of breast cancers expressing endocrine-refractory ESR1 mutations. Using a newly developed anti-pS294 monoclonal antibody, a combination of CDK specific siRNA knockdown studies and a broad panel of CDK selective inhibitors against ligand (E2)-stimulated MCF7 cells, we first identified CDK2 as the primary mediator of pS294 formation and showed that CDK2-selective inhibitors like Dinaciclib, but not CDK4/6 inhibitors like Palbociclib, can selectively prevent pS294 formation and repress ER-dependent gene expression...
October 18, 2016: Oncotarget
Daniel Nava Rodrigues, Gunther Boysen, Semini Sumanasuriya, George Seed, Angelo M De Marzo, Johann de Bono
Prostate cancer (PCa) is a clinically heterogeneous disease and current treatment strategies are based largely on anatomical and pathological parameters. In the recent past, several DNA sequencing studies of primary and advanced PCa have revealed recurrent patterns of genomic aberrations that expose mechanisms of resistance to available therapies and potential new drug targets. Suppression of androgen receptor (AR) signalling is the cornerstone of advanced prostate cancer treatment. Genomic aberrations of the androgen receptor or alternative splicing of its mRNA are increasingly recognized as biomarkers of resistance to AR-targeted therapy such as abiraterone or enzalutamide...
October 18, 2016: Journal of Pathology
C Yang, Z Li, T Bhatt, M Dickler, D Giri, M Scaltriti, J Baselga, N Rosen, S Chandarlapaty
Dysregulated activation of the CDK4/6 kinases is a hallmark of most mammary-derived carcinomas. ATP-competitive inhibitors against this complex have been recently advanced in the clinic and have shown significant activity, particularly against tumors driven by the estrogen receptor (ER). However, resistance to these compounds has begun to emerge often months to years after their initiation. We investigated potential mechanisms of resistance using cell line models that are highly sensitive to this class of drugs...
October 17, 2016: Oncogene
Dimitrios Zardavas, Konstantinos Tryfonidis, Theodora Goulioti, Martine Piccart
INTRODUCTION: The potential of molecular targeted therapy to improve the clinical outcomes of patients with early-stage breast cancer (BC) as adjuvant therapy has been first demonstrated through endocrine treatment. The introduction of HER2 blockade, through the successful clinical development of trastuzumab, changed the natural history of HER2-positive BC subtype. AREAS COVERED: There are ongoing efforts to augment further the use of targeted agents as adjuvant treatment in BC, hoping that early introduction of targeted therapy blocking key oncogenic drivers of micro-residual disease, will significantly improve clinical outcomes...
October 14, 2016: Expert Review of Anticancer Therapy
Lori S Hart, JulieAnn Rader, Pichai Raman, Vandana Batra, Michael R Russell, Matthew Tsang, Maria Gagliardi, Lucy Chen, Daniel Martinez, Yimei Li, Andrew Wood, Sunkyu Kim, Sudha Parasuraman, Scott Delach, Kristina A Cole, Shiva Krupa, Markus Boehm, Malte Peters, Giordano Caponigro, John M Maris
PURPOSE: Neuroblastoma is treated with aggressive multi-modal therapy, yet more than 50% of patients experience relapse. We recently showed that relapsed neuroblastomas frequently harbor mutations leading to hyperactivated ERK signaling and sensitivity to MEK inhibition therapy. Here we sought to define a synergistic therapeutic partner to potentiate MEK inhibition. EXPERIMENTAL DESIGN: We first surveyed 22 genetically annotated human neuroblastoma-derived cell lines (from 20 unique patients) for sensitivity to the MEK inhibitor binimetinib...
October 11, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Kyun Ha Kim, Chang-Woo Han, Seong Hoon Yoon, Yun Seong Kim, Jong-In Kim, Myungsoo Joo, Jun-Yong Choi
Lung cancer has substantial mortality worldwide, and chemotherapy is a routine regimen for the treatment of patients with lung cancer, despite undesirable effects such as drug resistance and chemotoxicity. Here, given a possible antitumor effect of the fruit hull of Gleditsia sinensis (FGS), we tested whether FGS enhances the effectiveness of cis-diammine dichloridoplatinum (II) (CDDP), a chemotherapeutic drug. We found that CDDP, when administered with FGS, significantly decreased the viability and increased the apoptosis and cell cycle arrest of Lewis lung carcinoma (LLC) cells, which were associated with the increase of p21 and decreases of cyclin D1 and CDK4...
2016: Evidence-based Complementary and Alternative Medicine: ECAM
Cornelia Liedtke, Hans-Christian Kolberg
Systemic therapy of metastatic breast cancer may include chemotherapy, endocrine therapy, and targeted therapies (e.g., antibody-based approaches). These agents may be employed alone or in combination based on the patient's breast cancer subtype. Therefore, characterization of the disease phenotype is necessary and may include biopsy of the metastatic site. Novel therapeutic approaches include immunologic therapies, PARP inhibitors, PI3K inhibitors, and CDK4/6 inhibitors, which are currently under investigation in clinical trials...
August 2016: Breast Care
Gabriel N Hortobagyi, Salomon M Stemmer, Howard A Burris, Yoon-Sim Yap, Gabe S Sonke, Shani Paluch-Shimon, Mario Campone, Kimberly L Blackwell, Fabrice André, Eric P Winer, Wolfgang Janni, Sunil Verma, Pierfranco Conte, Carlos L Arteaga, David A Cameron, Katarina Petrakova, Lowell L Hart, Cristian Villanueva, Arlene Chan, Erik Jakobsen, Arnd Nusch, Olga Burdaeva, Eva-Maria Grischke, Emilio Alba, Erik Wist, Norbert Marschner, Anne M Favret, Denise Yardley, Thomas Bachelot, Ling-Ming Tseng, Sibel Blau, Fengjuan Xuan, Farida Souami, Michelle Miller, Caroline Germa, Samit Hirawat, Joyce O'Shaughnessy
Background The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2). Methods In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease...
October 7, 2016: New England Journal of Medicine
Liang Wei, Brian J Leibowitz, Xinwei Wang, Michael Epperly, Joel Greenberger, Lin Zhang, Jian Yu
Radiotherapy causes dose-limiting toxicity and long-term complications in rapidly renewing tissues, including the gastrointestinal tract. Currently, there is no FDA-approved agent for the prevention or treatment of radiation-induced intestinal injury. In this study, we have shown that PD 0332991 (PD), an FDA-approved selective inhibitor of cyclin-dependent kinase 4/6 (CDK4/6), prevents radiation-induced lethal intestinal injury in mice. Treating mice with PD or a structurally distinct CDK4/6 inhibitor prior to radiation blocked proliferation and crypt apoptosis and improved crypt regeneration...
October 4, 2016: Journal of Clinical Investigation
(no author information available yet)
No abstract text is available yet for this article.
October 1, 2016: Cancer Research
D T Saenz, W Fiskus, T Manshouri, K Rajapakshe, S Krieger, B Sun, C P Mill, C DiNardo, N Pemmaraju, T Kadia, S Parmar, S Sharma, C Coarfa, P Qiu, S Verstovsek, K N Bhalla
Myeloproliferative Neoplasms with myelofibrosis (MPN-MF) demonstrate constitutive activation of JAK-STAT signaling, which responds to treatment with the JAK1 & 2 kinase inhibitor (JAKi) ruxolitinib. However, MPN-MF often progresses (~20%) to secondary AML (sAML), where standard induction chemotherapy or ruxolitinib is relatively ineffective, necessitating the development of novel therapeutic approaches. In the present studies, we demonstrate that treatment with BET (bromodomain and extra terminal) protein inhibitor (BETi), e...
September 28, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Gwang Hun Park, Ji Ho Sung, Hun Min Song, Jin Boo Jeong
BACKGROUND: Psoralea Fructus (PF), the dried and ripe fruit of Psoralea corylifolia exhibits an anti-cancer activity. However, the molecular mechanisms by which PF inhibits the proliferation of cancer cells have not been elucidated in detail. Cyclin D1 and CDK4 are important regulatory proteins in cell growth and are overexpressed in many cancer cells. In this study, we investigated the molecular mechanism of PF on the downregulation of cyclin D1 and CDK4 level. METHODS: Cell growth was evaluated by MTT assay...
September 26, 2016: BMC Complementary and Alternative Medicine
Maren Feist, Judith Kemper, Franziska Taruttis, Thorsten Rehberg, Julia C Engelmann, Wolfram Gronwald, Michael Hummel, Rainer Spang, Dieter Kube
A network of autocrine and paracrine signals defines B cell homeostasis and is thought to be involved in transformation processes. Investigating interactions of these microenvironmental factors and their relation to proto-oncogenes as c-Myc (MYC) is fundamental to understand the biology of B cell lymphoma. Therefore, B cells with conditional MYC expression were stimulated with CD40L, insulin-like growth factor 1, α-IgM, Interleukin-10 (IL10) and CpG alone or in combination. The impact of forty different interventions on cell proliferation was investigated in MYC deprived cells and calculated by linear regression...
September 26, 2016: International Journal of Cancer. Journal International du Cancer
Hai Ha Thi Pham, Yeong-Ae Seong, Chul-Woong Oh, Gun-Do Kim
Cyperus amuricus (C. amuricus) is one of the most common herbs in Oriental folk medicine for exerting astringent, diuretic, wound healing and other intestinal problems. However, little is known about the molecular mechanism of C. amuricus on anticancer activity. In the present study, the underlying mechanism of the anticancer effect of C. amuricus were elucidated. The methyl alcohol extract from the whole plant of C. amuricus exhibited cytotoxicity against Hep3B cells, but not against A549 and HaCaT cells...
September 20, 2016: International Journal of Oncology
Yujing Tian, Mengwen Qi, Zhiwen Hong, Yingchun Li, Yibiao Yuan, Yimei Du, Lei Chen, Ling Chen
Neurogenesis plays an important role in adult hippocampal function, and this process can be modulated by intracellular calcium. The activation of transient receptor potential vanilloid 4 (TRPV4) induces an increase in intracellular calcium concentration, but whether neurogenesis can be modulated by TRPV4 activation remains unclear. Here, we report that intracerebroventricular injection of the TRPV4 agonist GSK1016790A for 5 days enhanced the proliferation of stem cells in the hippocampal dentate gyrus (DG) of adult mice without affecting neurite growth, differentiation, or survival of newborn cells...
September 22, 2016: Molecular Neurobiology
Luca Malorni, Silvano Piazza, Yari Ciani, Cristina Guarducci, Martina Bonechi, Chiara Biagioni, Christopher D Hart, Roberto Verardo, Angelo Di Leo, Ilenia Migliaccio
Palbociclib is a CDK4/6 inhibitor that received FDA approval for treatment of hormone receptor positive (HR+) HER2 negative (HER2neg) advanced breast cancer. To better personalize patients treatment it is critical to identify subgroups that would mostly benefit from it. We hypothesize that complex alterations of the Retinoblastoma (Rb) pathway might be implicated in resistance to CDK4/6 inhibitors and aim to investigate whether signatures of Rb loss-of-function would identify breast cancer cell lines resistant to palbociclib...
September 13, 2016: Oncotarget
Carmen Di Giovanni, Ettore Novellino, Adriana Chilin, Antonio Lavecchia, Giovanni Marzaro
INTRODUCTION: Cell cycle and gene transcription are under the control of cyclin-dependent kinases (CDKs), whose activity depends on the binding with cyclins. Deregulated CDK activities have been reported in a majority of human cancers, representing potential therapeutic targets. AREAS COVERED: This review provides preclinical and clinical (phase I/II) updates of promising therapeutic compounds targeting CDKs published between 2013 and 2016 Expert opinion: First generation pan-CDK inhibitors showed marked toxicity in clinical trials and most compounds were discontinued...
October 2016: Expert Opinion on Investigational Drugs
Erik S Knudsen, Agnieszka K Witkiewicz
ER positive (ER+) and HER2 negative (HER2-) breast cancers are routinely treated based on estrogen dependence. CDK4/6 inhibitors in combination with endocrine therapy have significantly improved the progression-free survival of patients with ER+/HER2- metastatic breast cancer. Gene expression profiling in ER+/HER2- models was used to define the basis for the efficacy of CDK4/6 inhibitors and develop a gene expression signature of CDK4/6 inhibition. CDK4/6 inhibition robustly suppressed cell cycle progression of ER+/HER2- models and complements the activity of limiting estrogen...
August 18, 2016: Oncotarget
Rekha Gyanchandani, Karthik J Kota, Amruth R Jonnalagadda, Tanya Minteer, Beth A Knapick, Steffi Oesterreich, Adam M Brufsky, Adrian V Lee, Shannon L Puhalla
ESR1 mutations are frequently acquired in hormone-resistant metastatic breast cancer (MBC). CDK4/6 inhibition along with endocrine therapy is a promising strategy in hormone receptor-positive MBC. However, the incidence and impact of ESR1 mutations on clinical outcome in patients treated with CDK4/6 inhibitors have not been defined. In this study, we evaluated the frequency of ESR1 mutations in cfDNA from 16 patients with MBC undergoing palbociclib and letrozole therapy. Four common ESR1 mutations (D538G, Y537C, Y537N, and Y537S) were analyzed in serial blood draws using ddPCR...
August 19, 2016: Oncotarget
Xiaodong Liu, Shuo Tian, Mei Liu, Lingyan Jian, Limei Zhao
The anticancer effects of the natural flavonoid, wogonin, have been reported. However, its molecular mechanisms of action have not yet been fully explored. In the present study, we aimed to examine the molecular mechanisms of action of wogonin and its effects on the biological behavior of the HepG2 and Bel7402 hepatocellular carcinoma (HCC) cell lines. We also examined the effects of wogonin on nuclear factor-κB (NF-κB)/Bcl-2 and epidermal growth factor receptor (EGFR) signaling, as well as on downstream pathways of EGFR, namely extracellular signal-regulated kinase (ERK)/AKT signaling...
October 2016: International Journal of Molecular Medicine
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