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CDK4/6 Inhibitors

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https://www.readbyqxmd.com/read/29352052/estrogen-receptor-positive-breast-cancer-exploiting-signaling-pathways-implicated-in-endocrine-resistance
#1
REVIEW
Adam M Brufsky, Maura N Dickler
Advancements in molecular profiling and endocrine therapy (ET) have led to more focused clinical attention on precision medicine. These advances have expanded our understanding of breast cancer (BC) pathogenesis and hold promising implications for the future of therapy. The estrogen receptor-α is a predominant endocrine regulatory protein in the breast and in estrogen-induced BC. Successful targeting of proteins and genes within estrogen receptor (ER) nuclear and nonnuclear pathways remains a clinical goal...
January 19, 2018: Oncologist
https://www.readbyqxmd.com/read/29349755/adjuvant-endocrine-therapy
#2
Rena Shah, Ruth M O'Regan
The use of hormonal therapy in breast cancer has improved the overall outcome for patients with early-stage hormone receptor-positive disease. The choice of hormone therapy is related to multiple factors, including menopausal state, patient preference, and potential side effects. Molecular profiling has allowed therapy to be tailored for an individual patient to some extent. However, further molecular studies are needed to individualize the choice and length of adjuvant hormone therapy. Ongoing studies are evaluating the role of additional targeted therapies, such as CDK4/6 inhibitors, to further improve outcome for patients with early-stage hormone receptor-positive breast cancer...
2018: Cancer Treatment and Research
https://www.readbyqxmd.com/read/29335521/non-canonical-roles-of-pfkfb3-in-regulation-of-cell-cycle-through-binding-to-cdk4
#3
Wenzhi Jia, Xiaoping Zhao, Li Zhao, Hui Yan, Jiajin Li, Hao Yang, Gang Huang, Jianjun Liu
There is growing interest in studying the molecular mechanisms of crosstalk between cancer metabolism and the cell cycle. 6-phosphate fructose-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) is a well-known glycolytic activator that plays an important role in tumorigenesis. We investigated whether PFKFB3 was directly involved in oncogenic signaling networks. Mass Spectrometry showed that PFKFB3 interacts with cyclin-dependent kinase (CDK) 4, which controls the transition from G1 phase to S phase of the cell cycle...
January 16, 2018: Oncogene
https://www.readbyqxmd.com/read/29330290/dual-inhibition-of-cdk4-and-cdk2-via-targeting-p27-tyrosine-phosphorylation-induces-a-potent-and-durable-response-in-breast-cancer-cells
#4
Priyank Patel, Vladislav Tsiperson, Susan R S Gottesman, Jonathan Somma, Stacy W Blain
Cyclin-dependent kinase 4/6 (CDK4/6) specific inhibitors, such as Palbociclib, have shown clinical efficacy, but primary or secondary resistance has emerged as a problem. To develop more effective therapeutic approaches, investigation is needed into the mechanisms of resistance or adaption. Here, it is demonstrated that CDK2 compensates for loss of CDK4 activity to rescue Palbociclib-arrested breast cancer cells, suggesting that inhibition of both kinases is required to achieve durable response. In addition, a novel strategy is described to inhibit tyrosine phosphorylation of p27Kip1 (CDKN1B) and simultaneously inhibit both CDK2 and CDK4...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29311118/therapeutic-challenge-with-a-cdk-4-6-inhibitor-induces-an-rb-dependent-smac-mediated-apoptotic-response-in-non-small-cell-lung-cancer
#5
Chellappagounder Thangavel, Ettickan Boopathi, Yi Liu, Christopher McNair, Alex Haber, Maryna Perepelyuk, Anshul Bhardwaj, Sankar Addya, Adam Ertel, Sunday Shoyele, Ruth Birbe, Joseph M Salvino, Adam P Dicker, Karen E Knudsen, Robert B Den
The retinoblastoma tumor suppressor (RB), a key regulator of cell cycle progression and proliferation, is functionally suppressed in up to 50% of non-small cell lung cancer (NSCLC).  RB function is exquisitely controlled by a series of proteins including the CyclinD-CDK4/6 complex. In the current study, we interrogated the capacity of a CDK4/6 inhibitor, palbociclib, to activate RB function.   Experimental Design and Results: We employed multiple isogenic RB proficient and deficient NSCLC lines to interrogate the cytostatic and cytotoxic capacity of CDK 4/6 inhibition in vitro and in vivo  We demonstrate that while short term exposure to palbociclib induces cellular senescence, prolonged exposure results in inhibition of tumor growth...
January 8, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29306194/downregulation-of-parp1-transcription-by-cdk4-6-inhibitors-sensitizes-human-lung-cancer-cells-to-anticancer-drug-induced-death-by-impairing-ogg1-dependent-base-excision-repair
#6
Dominika Tempka, Paulina Tokarz, Kinga Chmielewska, Magdalena Kluska, Julita Pietrzak, Żaneta Rygielska, László Virág, Agnieszka Robaszkiewicz
Hallmarks of cancer cells include uncontrolled growth and rapid proliferation; thus, cyclin-dependent kinases are a therapeutic target for cancer treatment. Treating non-small lung cancer cells with sublethal concentrations of the CDK4/6 inhibitors, ribociclib (LEE011) and palbociclib (PD0332991), which are approved by the FDA for anticancer therapies, caused cell cycle arrest in the G1 phase and suppression of poly(ADP-ribose) polymerase 1 (PARP1) transcription by inducing recruitment of the RB1-E2F1-HDAC1-EZH2 repressive complex to the PARP1 promoter...
December 29, 2017: Redox Biology
https://www.readbyqxmd.com/read/29306020/a-selective-cyclin-dependent-kinase-4-6-dual-inhibitor-ribociclib-lee011-inhibits-cell-proliferation-and-induces-apoptosis-in-aggressive-thyroid-cancer
#7
Hyun Joo Lee, Woo Kyung Lee, Chan Woo Kang, Cheol Ryong Ku, Yoon Hee Cho, Eun Jig Lee
The RB-E2F1 pathway is an important mechanism of cell-cycle control, and deregulation of this pathway is one of the key factors contributing to tumorigenesis. Cyclin-dependent kinases (CDKs) and Cyclin D have been known to increase in aggressive thyroid cancer. However, there has been no study to investigate effects of a selective CDK 4/6 inhibitor, Ribociclib (LEE011), in thyroid cancer. Performing Western blotting, we found that RB phosphorylation and the expression of Cyclin D are significantly higher in papillary thyroid cancer (PTC) cell lines as well as anaplastic thyroid cancer (ATC) cell lines, compared with normal thyroid cell line and follicular thyroid cancer cell line...
January 3, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29291023/combined-venetoclax-and-alvocidib-in-acute-myeloid-leukemia
#8
James Bogenberger, Clifford Whatcott, Nanna Hansen, Devora Delman, Chang-Xin Shi, Wontak Kim, Hillary Haws, Katherine Soh, Ye Sol Lee, Peter Peterson, Adam Siddiqui-Jain, Steven Weitman, Keith Stewart, David Bearss, Ruben Mesa, Steven Warner, Raoul Tibes
More effective treatment options for elderly acute myeloid leukemia (AML) patients are needed as only 25-50% of patients respond to standard-of-care therapies, response duration is typically short, and disease progression is inevitable even with some novel therapies and ongoing clinical trials. Anti-apoptotic BCL-2 family inhibitors, such as venetoclax, are promising therapies for AML. Nonetheless, resistance is emerging. We demonstrate that venetoclax combined with cyclin-dependent kinase (CDK) inhibitor alvocidib is potently synergistic in venetoclax-sensitive and -resistant AML models in vitro, ex vivo and in vivo...
December 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/29283884/a-hypothesis-driven-approach-identifies-cdk4-and-cdk6-inhibitors-as-candidate-drugs-for-treatments-of-adrenocortical-carcinomas
#9
Djihad Hadjadj, Su-Jung Kim, Thomas Denecker, Laura Ben Driss, Jean-Charles Cadoret, Chrystelle Maric, Giuseppe Baldacci, Fabien Fauchereau
High proliferation rate and high mutation density are both indicators of poor prognosis in adrenocortical carcinomas. We performed a hypothesis-driven association study between clinical features in adrenocortical carcinomas and the expression levels of 136 genes involved in DNA metabolism and G1/S phase transition. In 79 samples downloaded from The Cancer Genome Atlas portal, high Cyclin Dependent Kinase 6 (CDK6) mRNA levels gave the most significant association with shorter time to relapse and poorer survival of patients...
December 26, 2017: Aging
https://www.readbyqxmd.com/read/29282688/cell-cycle-regulation-in-treatment-of-breast-cancer
#10
Zijie Cai, Qiang Liu
Cell cycle progression and cell proliferation are under precise and orchestrated control in normal cells. However, uncontrolled cell proliferation caused by aberrant cell cycle progression is a crucial characteristic of cancer. Understanding cell cycle progression and its regulation sheds light on cancer treatment. Agents targeting cell cycle regulators (such as CDKs) have been considered as promising candidates in cancer treatment. Although the first-generation pan-CDK inhibitors failed in clinical trials because of their adverse events and low efficacy, new selective CDK 4/6 inhibitors showed potent efficacy with tolerable safety in preclinical and clinical studies...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29261702/combination-of-palbociclib-with-enzalutamide-shows-in-vitro-activity-in-rb-proficient-and-androgen-receptor-positive-triple-negative-breast-cancer-cells
#11
Chun-Yu Liu, Ka-Yi Lau, Chia-Chi Hsu, Ji-Lin Chen, Chia-Han Lee, Tzu-Ting Huang, Yi-Ting Chen, Chun-Teng Huang, Po-Han Lin, Ling-Ming Tseng
OBJECTIVES: Triple negative breast cancer (TNBC) lacks specific drug targets and remains challenging. Palbociclib, a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor is approved for metastatic estrogen receptor (ER)-positive and human epithermal growth factor 2 (HER2)-negative breast cancer. The nature of cell cycle inhibition by palbociclib suggests its potential in TNBC cells. Retinoblastoma (RB, a known substrate of CDK4/6) pathway deregulation is a frequent occurrence in TNBC and studies have revealed that pharmacological CDK4/6 inhibition induces a cooperative cytostatic effect with doxorubicin in RB-proficient TNBC models...
2017: PloS One
https://www.readbyqxmd.com/read/29250202/asco-2017-highlights-in-breast-cancer
#12
REVIEW
Rupert Bartsch, Elisabeth Bergen
At the 2017 ASCO Annual Meeting, several pertinent studies in the field of breast cancer were presented and some are deemed as being potentially practice changing. BrighTNess was the first phase III study to investigate the addition of carboplatin to standard neoadjuvant chemotherapy in triple-negative breast cancer; while toxicity was increased in the experimental group, a significantly higher pathologic complete remission (pCR) rate was observed as well suggesting that adding carboplatin to neoadjuvant anthracycline, cyclophosphamide and taxane-containing regimens is efficacious in otherwise healthy patients...
2017: Memo
https://www.readbyqxmd.com/read/29247857/a-highly-potent-cdk4-6-inhibitor-was-rationally-designed-to-overcome-blood-brain-barrier-in-gliobastoma-therapy
#13
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
https://www.readbyqxmd.com/read/29247442/efficacy-of-palbociclib-plus-fulvestrant-after-everolimus-in-hormone-receptor-positive-metastatic-breast-cancer
#14
Pauline du Rusquec, Clément Palpacuer, Loic Campion, Anne Patsouris, Paule Augereau, Carole Gourmelon, Marie Robert, Laurence Dumas, Folliard Caroline, Mario Campone, Jean-Sébastien Frenel
BACKGROUND: Palbociclib, a CDK4-6 inhibitor, combined with endocrine therapy (ET) is a new standard of treatment for Hormone Receptor-positive Metastatic Breast Cancer. We present the first real-life efficacy and tolerance data of palbociclib plus fulvestrant in this population. METHODS: From November 2015 to November 2016, patients receiving in our institution palbociclib + fulvestrant according to the Temporary Authorization for Use were prospectively analyzed...
December 15, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29247039/h3b-6527-is-a-potent-and-selective-inhibitor-of-fgfr4-in-fgf19-driven-hepatocellular-carcinoma
#15
Jaya Julie Joshi, Heather Coffey, Erik Corcoran, Jennifer Tsai, Chia-Ling Huang, Kana Ichikawa, Sudeep Prajapati, Ming-Hong Hao, Suzanna Bailey, Jeremy Wu, Victoria Rimkunas, Craig Karr, Vanitha Subramanian, Pavan Kumar, Crystal MacKenzie, Raelene Hurley, Takashi Satoh, Kun Yu, Eunice Park, Nathalie Rioux, Amy Kim, Weidong G Lai, Lihua Yu, Ping Zhu, Silvia Buonamici, Nicholas Larsen, Peter Fekkes, John Wang, Markus Warmuth, Dominic J Reynolds, Peter G Smith, Anand Selvaraj
Activation of the fibroblast growth factor receptor FGFR4 by FGF19 drives hepatocellular carcinoma (HCC), a disease with few, if any, effective treatment options. While a number of pan-FGFR inhibitors are being clinically evaluated, their application to FGF19-driven HCC may be limited by dose-limiting toxicities mediated by FGFR1-3 receptors. To evade the potential limitations of pan-FGFR inhibitors, we generated H3B-6527, a highly selective covalent FGFR4 inhibitor, through structure-guided drug design. Studies in a panel of 40 HCC cell lines and 30 HCC PDX models showed that FGF19 expression is a predictive biomarker for H3B-6527 response...
December 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/29245989/cdk4-6-dual-inhibitor-abemaciclib-demonstrates-compelling-preclinical-activity-against-esophageal-adenocarcinoma-a-novel-therapeutic-option-for-a-deadly-disease
#16
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
https://www.readbyqxmd.com/read/29243224/palbociclib-synergizes-with-braf-and-mek-inhibitors-in-treatment-na%C3%A3-ve-melanoma-but-not-after-the-development-of-braf-inhibitor-resistance
#17
Claire A Martin, Carleen Cullinane, Laura Kirby, Shatha Abuhammad, Emily J Lelliott, Kelly Waldeck, Richard J Young, Natalie Brajanovski, Donald P Cameron, Rachael Walker, Elaine Sanij, Gretchen Poortinga, Ross D Hannan, Richard B Pearson, Rodney J Hicks, Grant A McArthur, Karen E Sheppard
Increased CDK4 activity occurs in the majority of melanomas and CDK4/6 inhibitors in combination with BRAF and MEK inhibitors are currently in clinical trials for the treatment of melanoma. We hypothesize that the timing of the addition of CDK4/6 inhibitors to the current BRAF and MEK inhibitor regime will impact on the efficacy of this triplet drug combination. The efficacy of BRAF, MEK and CDK4/6 inhibitors as single agents and in combination were assessed in human BRAF mutant cell lines that were treatment naïve, BRAF inhibitor tolerant or had acquired resistance to BRAF inhibitors...
December 15, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29236940/polyclonal-rb1-mutations-and-acquired-resistance-to-cdk-4-6-inhibitors-in-patients-with-metastatic-breast-cancer
#18
R Condorelli, L Spring, J O'Shaughnessy, L Lacroix, C Bailleux, V Scott, J Dubois, R J Nagy, R B Lanman, A J Iafrate, F Andre, A Bardia
Background: While deregulation of the cyclin D1-CDK4/6-retinoblastoma pathway is common in hormone receptor positive (HR+) breast cancer, Rb is usually intact in HR+ breast cancer, and targeted CDK 4/6 inhibitors that act upstream of Rb, are routinely being utilized in clinical practice. However, factors that can lead to clinical resistance to CDK 4/6 inhibitors are not known. Patients and methods: We identified patients who had pre and post genotyping in tissue and peripheral blood samples after receiving CDK 4/6 inhibitors...
December 11, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29236235/potential-biomarkers-of-cdk4-6-inhibitors-in-hormone-receptor-positive-advanced-breast-cancer
#19
REVIEW
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
https://www.readbyqxmd.com/read/29234249/mechanisms-of-resistance-to-cdk4-6-inhibitors-in-breast-cancer-and-potential-biomarkers-of-response
#20
REVIEW
Cristina Guarducci, Martina Bonechi, Giulia Boccalini, Matteo Benelli, Emanuela Risi, Angelo Di Leo, Luca Malorni, Ilenia Migliaccio
Randomized clinical trials demonstrated that CDK4/6 inhibitors are highly effective in patients with hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer in combination with endocrine therapy. The use of CDK4/6 inhibitors in clinics is becoming common for patients with HR+/HER2- metastatic breast cancer and will certainly increase in the near future. However, patients might show de novo or acquired resistance to these drugs. Molecular alterations have been suggested as determinants for de novo resistance to CDK4/6 inhibitors, but have never been validated in a clinical setting...
October 2017: Breast Care
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