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CDK4/6 Inhibitors

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https://www.readbyqxmd.com/read/27923036/cotargeting-of-cyp-19-aromatase-and-emerging-pivotal-signalling-pathways-in-metastatic-breast-cancer
#1
REVIEW
Stine Daldorff, Randi Margit Ruud Mathiesen, Olav Erich Yri, Hilde Presterud Ødegård, Jürgen Geisler
Aromatase inhibition is one of the cornerstones of modern endocrine therapy of oestrogen receptor-positive (ER+) metastatic breast cancer (MBC). The nonsteroidal aromatase inhibitors anastrozole and letrozole, as well as the steroidal aromatase inactivator exemestane, are the preferred drugs and established worldwide in all clinical phases of the disease. However, although many patients suffering from MBC experience an initial stabilisation of their metastatic burden, drug resistance and disease progression occur frequently, following in general only a few months on treatment...
December 6, 2016: British Journal of Cancer
https://www.readbyqxmd.com/read/27903275/cell-cycle-inhibition-reduces-inflammatory-responses-neuronal-loss-and-cognitive-deficits-induced-by-hypobaria-exposure-following-traumatic-brain-injury
#2
Jacob W Skovira, Junfang Wu, Jessica J Matyas, Alok Kumar, Marie Hanscom, Shruti V Kabadi, Raymond Fang, Alan I Faden
BACKGROUND: Traumatic brain injury (TBI) patients in military settings can be exposed to prolonged periods of hypobaria (HB) during aeromedical evacuation. Hypobaric exposure, even with supplemental oxygen to prevent hypoxia, worsens outcome after experimental TBI, in part by increasing neuroinflammation. Cell cycle activation (CCA) after TBI has been implicated as a mechanism contributing to both post-traumatic cell death and neuroinflammation. Here, we examined whether hypobaric exposure in rats subjected to TBI increases CCA and microglial activation in the brain, as compared to TBI alone, and to evaluate the ability of a cyclin-dependent kinase (CDK) inhibitor (CR8) to reduce such changes and improve behavioral outcomes...
December 1, 2016: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/27883943/targeted-therapy-for-breast-cancer-and-molecular-mechanisms-of-resistance-to-treatment
#3
REVIEW
Guowei Gu, Derek Dustin, Suzanne Aw Fuqua
In recent years, clinical trials investigating new drugs and therapeutic combinations have led to promising advances in breast cancer therapy. Subtyping breast cancers into hormone receptor (HR) positive, epidermal growth factor receptor (HER2) positive, and triple negative breast cancer (TNBC) is currently the basis of diagnosing and treating this disease. In addition to endocrine and HER2-targeted therapies in their respective subtypes, evidence from recent preclinical studies have shown several targetable pathways that overcome resistance in the clinical setting...
November 21, 2016: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/27864574/enhancing-endocrine-therapy-combination-strategies-for-the-treatment-of-postmenopausal-hormone-receptor-positive-her2-advanced-breast-cancer
#4
REVIEW
Kathleen I Pritchard, Stephen K Chia, Christine Simmons, Deanna McLeod, Alexander Paterson, Louise Provencher, Daniel Rayson
: : Breast cancer (BC) is the most common malignancy in women worldwide, with approximately two-thirds having hormone receptor (HR)-positive tumors. New endocrine therapy (ET) strategies include combining ET agents as well as adding inhibitors targeting growth factors, angiogenesis, the mechanistic target of rapamycin, phosphoinositide 3-kinase (PI3K), or cyclin-dependent kinase 4/6 to ET. Level 1 evidence supports use of fulvestrant plus anastrozole or palbociclib plus letrozole as first-line therapy for HR-positive, HER2-negative advanced BC with special consideration for the former in ET-naïve patients, as well as everolimus plus exemestane or palbociclib plus fulvestrant as second-line therapy with special consideration in select first-line patients...
November 18, 2016: Oncologist
https://www.readbyqxmd.com/read/27864221/cyclin-d-mediates-tolerance-of-genome-doubling-in-cancers-with-functional-p53
#5
A Crockford, L P Zalmas, E Grönroos, S M Dewhurst, N McGranahan, M E Cuomo, V Encheva, A P Snijders, J Begum, S Purewal, J Cerveira, H Patel, M J Renshaw, C Swanton
BACKGROUND: Aneuploidy and chromosomal instability (CIN) are common features of human malignancy that fuel genetic heterogeneity. Although tolerance to tetraploidisation, an intermediate state that further exacerbates CIN, is frequently mediated by TP53 dysfunction, we find that some genome-doubled tumours retain wild-type TP53 We sought to understand how tetraploid cells with a functional p53/p21-axis tolerate genome-doubling events. METHODS: We performed quantitative proteomics in a diploid/tetraploid pair within a system of multiple independently-derived TP53 wild-type tetraploid clones arising spontaneously from a diploid progenitor...
November 17, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27849562/palbociclib-pd-0332991-a-selective-cdk4-6-inhibitor-restricts-tumour-growth-in-preclinical-models-of-hepatocellular-carcinoma
#6
Julien Bollard, Verónica Miguela, Marina Ruiz de Galarreta, Anu Venkatesh, C Billie Bian, Mark P Roberto, Victoria Tovar, Daniela Sia, Pedro Molina-Sánchez, Christie B Nguyen, Shigeki Nakagawa, Josep M Llovet, Yujin Hoshida, Amaia Lujambio
OBJECTIVE: Advanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Palbociclib, a well-tolerated and selective CDK4/6 inhibitor, has shown promising results in the treatment of retinoblastoma (RB1)-positive breast cancer. RB1 is rarely mutated in HCC, suggesting that palbociclib could potentially be used for HCC therapy. Here, we provide a comprehensive characterisation of the efficacy of palbociclib in multiple preclinical models of HCC. DESIGN: The effects of palbociclib on cell proliferation, cellular senescence and cell death were investigated in a panel of human liver cancer cell lines, in ex vivo human HCC samples, in a genetically engineered mouse model of liver cancer, and in human HCC xenografts in vivo...
November 14, 2016: Gut
https://www.readbyqxmd.com/read/27843622/review-of-hormone-based-treatments-in-postmenopausal-patients-with-advanced-breast-cancer-focusing-on-aromatase-inhibitors-and-fulvestrant
#7
REVIEW
Iben Kümler, Ann S Knoop, Christina A R Jessing, Bent Ejlertsen, Dorte L Nielsen
BACKGROUND: Endocrine therapy constitutes a central modality in the treatment of oestrogen receptor (ER)-positive advanced breast cancer. PURPOSE: To evaluate the evidence for endocrine treatment in postmenopausal patients with advanced breast cancer focusing on the aromatase inhibitors, letrozole, anastrozole, exemestane and fulvestrant. METHODS: A review was carried out using PubMed. Randomised phase II and III trials reporting on ≥100 patients were included...
2016: ESMO Open
https://www.readbyqxmd.com/read/27832204/expression-of-the-lncrna-maternally-expressed-gene-3-meg3-contributes-to-the-control-of-lung-cancer-cell-proliferation-by-the-rb-pathway
#8
Traci L Kruer, Susan M Dougherty, Lindsey Reynolds, Elizabeth Long, Tanya de Silva, William W Lockwood, Brian F Clem
Maternally expressed gene 3 (MEG3, mouse homolog Gtl2) encodes a long noncoding RNA (lncRNA) that is expressed in many normal tissues, but is suppressed in various cancer cell lines and tumors, suggesting it plays a functional role as a tumor suppressor. Hypermethylation has been shown to contribute to this loss of expression. We now demonstrate that MEG3 expression is regulated by the retinoblastoma protein (Rb) pathway and correlates with a change in cell proliferation. Microarray analysis of mouse embryonic fibroblasts (MEFs) isolated from mice with genetic deletion of all three Rb family members (TKO) revealed a significant silencing of Gtl2/MEG3 expression compared to WT MEFs, and re-expression of Gtl2/MEG3 caused decrease in cell proliferation and increased apoptosis...
2016: PloS One
https://www.readbyqxmd.com/read/27825114/pd-0332991-a-selective-cyclin-d-kinase-4-6-inhibitor-sensitizes-lung-cancer-cells-to-treatment-with-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitors
#9
Minghui Liu, Song Xu, Yuli Wang, Ying Li, Yongwen Li, Hongbing Zhang, Hongyu Liu, Jun Chen
Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is a major challenge to targeted therapy for non-small cell lung cancer (NSCLC). We investigated whether a cyclin D kinase 4/6 (CDK4/6) inhibitor, PD 0332991, could reverse EGFR-TKI resistance in human lung cancer cells and explored the underlying mechanisms. We found that PD 0332991 potentiated gefitinib-induced growth inhibition in both EGFR-TKI-sensitive (PC-9) and EGFR-TKI-resistant (PC-9/AB2) cells by down-regulating proliferation and inducing apoptosis and G0/G1 cell cycle arrest...
November 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27816766/fibroblast-growth-factor-9-fgf9-regulation-of-cyclin-d1-and-cyclin-dependent-kinase-4-in-ovarian-granulosa-and-theca-cells-of-cattle
#10
M L Totty, B C Morrell, L J Spicer
To determine the mechanism by which fibroblast growth factor 9 (FGF9) alters granulosa (GC) and theca (TC) cell proliferation, cell cycle proteins that regulate progression through G1 phase of the cell cycle, cyclin D1 (CCND1) and cyclin-dependent kinase-4 (CDK4; CCND1's catalytic partner), were evaluated. Ovaries were obtained from a local abattoir, GC were harvested from small (1-5 mm) and large (8-22 mm) follicles, and TC were harvested from large follicles. GC and TC were plated in medium containing 10% fetal calf serum followed by various treatments in serum-free medium...
November 3, 2016: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/27816545/effect-of-abemaciclib-ly2835219-on-enhancement-of-chemotherapeutic-agents-in-abcb1-and-abcg2-overexpressing-cells-in-vitro-and-in-vivo
#11
Tong Wu, Zhen Chen, Kenneth K W To, Xiaona Fang, Fang Wang, Bin Cheng, Liwu Fu
Multidrug resistance (MDR) is the major obstacle of the success in cancer chemotherapy. The overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1 and ABCG2, play a significant role in mediating MDR by pumping anticancer drugs out of cancer cells. Abemaciclib (LY2835219) is an orally bioavailable CDK4/6 inhibitor under phase III clinical trials. Here, we found that LY2835219 remarkably enhanced the efficacy of chemotherapeutic drugs in ABCB1 or ABCG2 over-expressing cancer cells in vitro and in vivo...
November 2, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27810861/ribociclib-lengthens-breast-cancer-survival
#12
(no author information available yet)
The combination of antiestrogen therapy and ribociclib, an investigational CDK4/6 inhibitor, led to improved outcomes in women with metastatic HR-positive, HER2-negative breast cancer, according to findings presented at a meeting of the European Society for Medical Oncology. The combination significantly increased progression-free survival compared with letrozole alone in a large phase III trial-data that could lead to FDA approval.
December 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27795451/3-deoxysappanchalcone-promotes-proliferation-of-human-hair-follicle-dermal-papilla-cells-and-hair-growth-in-c57bl-6-mice-by-modulating-wnt-%C3%AE-catenin-and-stat-signaling
#13
Young Eun Kim, Hyung Chul Choi, In-Chul Lee, Dong Yeon Yuk, Hyosung Lee, Bu Young Choi
3-Deoxysappanchalcone (3-DSC) has been reported to possess anti-allergic, antiviral, anti-inflammatory and antioxidant activities. In the present study, we investigated the effects of 3-DSC on the proliferation of human hair follicle dermal papilla cells (HDPCs) and mouse hair growth in vivo. A real-time cell analyzer system, luciferase assay, Western blot and real-time polymerase chain reaction (PCR) were employed to measure the biochemical changes occurring in HDPCs in response to 3-DSC treatment. The effect of 3-DSC on hair growth in C57BL/6 mice was also examined...
November 1, 2016: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/27785059/impact-of-palbociclib-combinations-on-treatment-of-advanced-estrogen-receptor-positive-human-epidermal-growth-factor-2-negative-breast-cancer
#14
REVIEW
Katalin Boér
Breast cancer is a heterogeneous disease with multiple subgroups based on clinical and molecular characteristics. For the largest subgroup of breast cancers, hormone receptor-positive/human epidermal growth factor 2 (HER2)-negative tumors, hormone treatment is the mainstay of therapy and is likely to result in significant improvement in disease outcomes. However, some of these cancers demonstrate de novo or acquired resistance to endocrine therapy. Despite intensive research to develop new strategies to enhance the efficacy of currently available treatment options for hormone receptor-positive breast cancer, progress has been slow, and there were few advances for a period of 10 years...
2016: OncoTargets and Therapy
https://www.readbyqxmd.com/read/27777309/her4-suppresses-p53-via-targeting-the-mdmx-mdm2-complex-implication-of-a-novel-mdmx-ser314-phosphosite
#15
Casimiro Gerarduzzi, Anna de Polo, Xue-Song Liu, Manale El Kharbili, John B Little, Zhi-Min Yuan
Deregulated receptor tyrosine kinase (RTK) signaling is frequently associated with tumorigenesis and therapy resistance, but its underlying mechanisms still need to be elucidated. In this study we have shown that the RTK human epidermal growth factor receptor 4 (Her4, aka Erbb4) can inhibit the tumor suppressor p53 by regulating the MDMX-MDM2 complex stabilization. Upon activation by either overexpression of a constitutively active vector or ligand binding (Neuregulin-1), Her4 was able to stabilize the MDMX-MDM2 complex resulting in suppression of p53 transcriptional activity, as shown by p53 responsive element-driven luciferase assay and mRNA levels of p53 target genes...
October 24, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27771926/potential-use-of-flavopiridol-in-treatment-of-chronic-diseases
#16
Thejal Srikumar, Jaya Padmanabhan
This chapter describes the potential use of flavopiridol, a CDK inhibitor with anti-inflammatory and anti-proliferative activities, in the treatment of various chronic diseases. Flavopiridol arrests cell cycle progression in the G1 or G2 phase by inhibiting the kinase activities of CDK1, CDK2, CDK4/6, and CDK7. Additionally, it binds tightly to CDK9, a component of the P-TEFb complex (CDK9/cyclin T), and interferes with RNA polymerase II activation and associated transcription. This in turn inhibits expression of several pro-survival and anti-apoptotic genes, and enhances cytotoxicity in transformed cells or differentiation in growth-arrested cells...
2016: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/27765908/erps294-is-a-biomarker-of-ligand-or-mutational-er%C3%AE-activation-and-a-breast-cancer-target-for-cdk2-inhibition
#17
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
https://www.readbyqxmd.com/read/27753448/the-molecular-underpinnings-of-prostate-cancer-impacts-on-management-and-pathology-practice
#18
REVIEW
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 recognised as biomarkers of resistance to AR-targeted therapies such as abiraterone or enzalutamide...
October 18, 2016: Journal of Pathology
https://www.readbyqxmd.com/read/27748766/acquired-cdk6-amplification-promotes-breast-cancer-resistance-to-cdk4-6-inhibitors-and-loss-of-er-signaling-and-dependence
#19
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
https://www.readbyqxmd.com/read/27729458/preclinical-therapeutic-synergy-of-mek1-2-and-cdk4-6-inhibition-in-neuroblastoma
#20
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
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