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David A Schaer, Richard P Beckmann, Jack A Dempsey, Lysiane Huber, Amelie Forest, Nelusha Amaladas, Yanxia Li, Ying Cindy Wang, Erik R Rasmussen, Darin Chin, Andrew Capen, Carmine Carpenito, Kirk A Staschke, Linda A Chung, Lacey M Litchfield, Farhana F Merzoug, Xueqian Gong, Philip W Iversen, Sean Buchanan, Alfonso de Dios, Ruslan D Novosiadly, Michael Kalos
Abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6), has recently been approved for the treatment of hormone receptor-positive breast cancer. In this study, we use murine syngeneic tumor models and in vitro assays to investigate the impact of abemaciclib on T cells, the tumor immune microenvironment and the ability to combine with anti-PD-L1 blockade. Abemaciclib monotherapy resulted in tumor growth delay that was associated with an increased T cell inflammatory signature in tumors. Combination with anti-PD-L1 therapy led to complete tumor regressions and immunological memory, accompanied by enhanced antigen presentation, a T cell inflamed phenotype, and enhanced cell cycle control...
March 13, 2018: Cell Reports
Elie El Rassy, Ziad Bakouny, Tarek Assi, Joseph Kattan
AIM: To determine which of the CDK4/6 inhibitors is the optimal treatment in metastatic luminal breast cancer. MATERIALS & METHODS: A network meta-analysis using the frequentist approach and generalized pairwise modeling was computed. RESULTS: The associations of aromatase inhibitor with ribociclib, palbociclib and abemaciclib were similar in efficacy. Palbociclib-based regimen was associated with significantly lower treatment discontinuation rates compared with the other approved drugs in this indication...
March 12, 2018: Future Oncology
Takeshi Kotake, Masakazu Toi
There have been numerous clinical trials of CDK4/6 inhibitors performed on various carcinomas including breast cancer. One such inhibitor tested and which has ongoing clinical trials for breast cancer is abemaciclib. Abemaciclib is a molecular-targeted agent that targets basic cell cycle regulatory mechanisms. Areas covered: This review discusses the available clinical data and ongoing clinical trials of abemaciclib in breast cancer. Expert opinion: Abemaciclib has demonstrated a clear anti-tumour effect and manageable toxicity against HR-positive, HER2-negative breast cancer in many clinical trials and is expected to be an important standard therapy...
March 9, 2018: Expert Opinion on Pharmacotherapy
Silvia Paola Corona, Daniele Generali
Although early breast cancer (BC) is highly curable, advanced or metastatic disease poses numerous challenges in terms of medical management and treatment decisions and is associated with significantly worse prognosis. Among the new targeted agents, anticancer drugs exploiting the cell-cycle machinery have shown great potential in preclinical studies. CDK4/6 inhibitors target the cyclin D/CDK/retinoblastoma signaling pathway, inducing cell-cycle arrest, reduced cell viability and tumor shrinking. As the cyclin D/CDK complex is activated downstream of estrogen signaling, the combination of CDK4/6 inhibitors with standard endocrine therapies represents a rational approach to elicit synergic antitumor activity in hormone receptor-positive BC...
2018: Drug Design, Development and Therapy
Neil O'Brien, Dylan Conklin, Richard Beckmann, Tong Luo, Kevin Chau, Josh Thomas, Ann Mc Nulty, Christophe Marchal, Ondrej Kalous, Erika von Euw, Sara Hurvitz, Colleen Mockbee, Dennis J Slamon
The cyclinD:CDK4/6:Rb axis is dysregulated in a variety of human cancers. Targeting this pathway has proven to be a successful therapeutic approach in ER+ breast cancer. In this study, in vitro and in vivo preclinical breast cancer models were used to investigate the expanded use of the CDK4/6 inhibitor, abemaciclib. Using a panel of 44 breast cancer cell lines, differential sensitivity to abemaciclib was observed and was seen predominately in the luminal ER+/HER2- and ER+/HER2+ subtypes. However, a subset of triple negative breast cancer (TNBC) cell lines with intact Rb-signaling were also found to be responsive...
February 26, 2018: Molecular Cancer Therapeutics
Allan Ramos-Esquivel, Hellen Hernández-Steller, Marie-France Savard, Denis Ulises Landaverde
BACKGROUND: To compare the efficacy and toxicity of the combination of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors and nonsteroidal aromatase inhibitors (AI) versus AI alone as first-line therapy for patients with advanced hormone receptor-positive breast cancer. MATERIALS AND METHODS: Phase III randomized clinical trials (RCT) were identified after a systematic review of electronic databases. A random-effect model was used to determine the pooled hazard ratio (HR) for progression-free survival (PFS) using the inverse-variance method...
February 22, 2018: Breast Cancer: the Journal of the Japanese Breast Cancer Society
Yan Wang, Wen-Jian Liu, Lei Yin, Heng Li, Zhen-Hua Chen, Dian-Xi Zhu, Xiu-Qing Song, Zhen-Zhen Cheng, Peng Song, Zhan Wang, Zhi-Gang Li
Cyclin-dependent kinases 4/6 play an important role in regulation of cell cycle, and overexpress in a variety of cancers. Up to now, new CDK inhibitors still need to be developed due to its poor selectivity. Herein we report a novel series of 4-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)-N-(5-(piperazin-1-ylmethyl)pyridine-2-yl)pyrimidin-2-amine anologues as potent CDK 4/6 inhibitors based on LY2835219 (Abemaciclib). Compound 10d, which exhibits approximate potency on CDK4/6 (IC50 = 7.4/0.9 nM), has both good pharmacokinetic characters and high selectivity on CDK1 compared with LY2835219...
January 31, 2018: Bioorganic & Medicinal Chemistry Letters
Hiroji Iwata
Endocrine therapy is the mainstay of treatment for patients with estrogen receptor positive (ER+)/HER2-negative (HER2-) metastatic breast cancer (MBC). Many clinicians consider the sequential endocrine therapy is gold standard strategy because of better outcome and the maintenance of a better quality of life (QOL) for MBC patients. However, clinical practice shall be changed according to development of CDK4/6 inhibitor in current. CDK4/6 is key kinase which promote the cell cycle, and especially the expression of cyclin D1 and the activation of CDK4/6 to drive breast cancer proliferation...
February 1, 2018: Breast Cancer: the Journal of the Japanese Breast Cancer Society
Tomasz Sarosiek
Cyclin-dependent kinases (CDKs) are a family of enzyme proteins present in cell nuclei that regulate the various stages of the cell cycle. They act as proto-oncogens, and increased expression of some of these proteins (CDK4 and CDK6) is observed in breast cancer cells and associated with decreased sensitivity to anti-estrogen therapy. CDK inhibitors are chemicals that inhibit the enzymatic activity of specific CDKs. Currently three drugs in this group are available on the market and are registered for the treatment of advanced HR-positive, HER2-negative breast cancer...
January 23, 2018: Polski Merkuriusz Lekarski: Organ Polskiego Towarzystwa Lekarskiego
Lei Yin, Heng Li, Wenjian Liu, Zhenglin Yao, Zhenzhen Cheng, Huabei Zhang, Hui Zou
Glioblastoma multiforme (GBM) is the most common and deadliest of malignant brain tumors in adults. Disease development is associated with dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway, resulting in increased proliferation; thus, CDK4/6 kinase inhibitors are promising candidates for GBM treatment. The recently developed CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, are effective in subcutaneous glioma models, but their blood-brain barrier (BBB) permeability is poor, limiting drug delivery to the central nervous system...
December 6, 2017: European Journal of Medicinal Chemistry
Juliann E Kosovec, Ali H Zaidi, Ashten N Omstead, Daisuke Matsui, Mark J Biedka, Erin J Cox, Patrick T Campbell, Robert W W Biederman, Ronan J Kelly, Blair A Jobe
Esophageal adenocarcinoma (EAC) is a deadly disease with limited therapeutic options. In the present study, we determined the preclinical efficacy of CDK4/6 inhibitor abemaciclib for treatment of EAC. In vitro, apoptosis, proliferation, and pathway regulation were evaluated in OE19, OE33, and FLO1 EAC cell lines. In vivo, esophagojejunostomy was performed on rats to induce EAC. At 36 weeks post-surgery, MRI and endoscopic biopsy established baseline tumor volume and molecular correlates, respectively. Next, the study animals were randomized to 26mg/kg intraperitoneal abemaciclib treatment or vehicle control for 28 days...
November 21, 2017: Oncotarget
Hehui Fang, Doudou Huang, Fang Yang, Xiaoxiang Guan
PURPOSE: Cyclin D/cyclin-dependent kinase 4/6 (CDK4/6) complex inhibitors have recently been proven effective when combined with endocrine therapy in clinical trials. However, the clinical benefit from CDK4/6 inhibitor varied from different patients. In order to optimize the clinical application of CDK4/6 inhibitors, this review focuses on the potential biomarkers applicable to identify patients who will benefit the most from CDK4/6 inhibition. METHODS: We have summarized the clinical trials about addition of CDK4/6 inhibitors to endocrine therapy and reviewed literature currently available on the potential biomarkers in predicting efficacy of CDK4/6 inhibitors...
December 13, 2017: Breast Cancer Research and Treatment
Xueqian Gong, Lacey M Litchfield, Yue Webster, Li-Chun Chio, Swee Seong Wong, Trent R Stewart, Michele Dowless, Jack Dempsey, Yi Zeng, Raquel Torres, Karsten Boehnke, Cecilia Mur, Carlos Marugán, Carmen Baquero, Chunping Yu, Steven M Bray, Isabella H Wulur, Chen Bi, Shaoyou Chu, Hui-Rong Qian, Philip W Iversen, Farhana F Merzoug, Xiang S Ye, Christoph Reinhard, Alfonso De Dios, Jian Du, Charles W Caldwell, María José Lallena, Richard P Beckmann, Sean G Buchanan
Most cancers preserve functional retinoblastoma (Rb) and may, therefore, respond to inhibition of D-cyclin-dependent Rb kinases, CDK4 and CDK6. To date, CDK4/6 inhibitors have shown promising clinical activity in breast cancer and lymphomas, but it is not clear which additional Rb-positive cancers might benefit from these agents. No systematic survey to compare relative sensitivities across tumor types and define molecular determinants of response has been described. We report a subset of cancers highly sensitive to CDK4/6 inhibition and characterized by various genomic aberrations known to elevate D-cyclin levels and describe a recurrent CCND1 3'UTR mutation associated with increased expression in endometrial cancer...
December 11, 2017: Cancer Cell
Geoffrey I Shapiro
In this issue of Cancer Cell, Gong et al. have analyzed the sensitivity of 560 cell lines to the selective CDK4/6 inhibitor abemaciclib and have defined cancers with specific genomic "D-cyclin activating features (DCAF)" as particularly vulnerable. These findings will facilitate patient selection as development of this drug class continues.
December 11, 2017: Cancer Cell
Jeffrey Small, Erik Washburn, Karmaine Millington, Junjia Zhu, Sheldon L Holder
Multiple therapies currently exist for renal cell carcinoma, however, most do not result in cure and the development of acquired resistance is the rule rather than the exception. CDK4/6 and PIM1 kinases are potential new therapeutic targets in RCC. Abemaciclib is a potent CDK4/6 and PIM1 kinase inhibitor, thus we evaluated the effects of abemaciclib on renal cell carcinoma. In vitro , abemaciclib causes decreased cellular viability, increased apoptosis, and alterations in autophagy in renal cell carcinoma cell lines...
November 10, 2017: Oncotarget
Iain Simpson
This industry update covers the period from 1 September through 30 September 2017, and is based on information sourced from company press releases, scientific literature, patents and various news websites. The month saw the US FDA approve three new molecular entities, Aliqopa (copanlisib dihydrochloride) (Bayer Healthcare); Solosec (secnidazole) (Symbiomix Therapeutics) and Verzenio (abemaciclib) (Eli Lilly and Co). Intarcia Therapeutics Inc. has its application for approval of a novel drug device combination of exenatide for the treatment of diabetes rejected by FDA but said that it will work to address the concerns and refile the application...
January 2018: Therapeutic Delivery
Rohini Rondla, Lavanya Souda PadmaRao, Vishwanath Ramatenki, Aboubakr Haredi-Abdel-Monsef, Sarita Rajender Potlapally, Uma Vuruputuri
The discovery of ATP competitive CDK4 inhibitors is an on-going challenging task in cancer therapy. Here, an attempt has been made to develop new leads targeting ATP binding site of CDK4 by applying 3D-QSAR pharmacophore mapping and molecular docking methods The outcome of 6 leads offers a significant contribution for selective CDK4 inhibition, since they show potential binding interactions with Val96 , Arg101 , and Glu144 residues of CDK4, that are unique and from other kinases. It is worth noting that there is a striking similarity in binding interactions of the leads and known CDK4 inhibitors, namely Abemaciclib, Palbociclib and Ribociclib...
December 2017: Computational Biology and Chemistry
Emily M Cousins, Dennis Goldfarb, Feng Yan, Jose Roques, David B Darr, Gary L Johnson, Michael B Major
The cellular and organismal phenotypic response to a small-molecule kinase inhibitor is defined collectively by the inhibitor's targets and their functions. The selectivity of small-molecule kinase inhibitors is commonly determined in vitro, using purified kinases and substrates. Recently, competitive chemical proteomics has emerged as a complementary, unbiased, cell-based methodology to define the target landscape of kinase inhibitors. Here, we evaluated and optimized a competitive multiplexed inhibitor bead mass spectrometry (MIB/MS) platform using cell lysates, live cells, and treated mice...
November 13, 2017: Molecular Cancer Research: MCR
Esther S Kim
Abemaciclib (Verzenio™) is an orally administered inhibitor of cyclin-dependent kinases 4 and 6 that is being developed by Eli Lilly and Company. Abemaciclib has been approved in the USA for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, in combination with fulvestrant in women with disease progression following endocrine therapy, and as monotherapy in adult patients with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting...
December 2017: Drugs
Kurt Engeland
Activation of the p53 tumor suppressor can lead to cell cycle arrest. The key mechanism of p53-mediated arrest is transcriptional downregulation of many cell cycle genes. In recent years it has become evident that p53-dependent repression is controlled by the p53-p21-DREAM-E2F/CHR pathway (p53-DREAM pathway). DREAM is a transcriptional repressor that binds to E2F or CHR promoter sites. Gene regulation and deregulation by DREAM shares many mechanistic characteristics with the retinoblastoma pRB tumor suppressor that acts through E2F elements...
November 10, 2017: Cell Death and Differentiation
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