Article
Oncology
Abeer J. Al-Qasem, Carla L. Alves, Sidse Ehmsen, Martina Tuttolomondo, Mikkel G. Terp, Lene E. Johansen, Henriette Vever, Luna V. A. Hoeg, Daniel Elias, Martin Bak, Henrik J. Ditzel
Summary: The upregulation of CDK6, p-CDK2, and/or cyclin E1 is associated with resistance to AI monotherapy and combined CDK4/6i and ET in ER+ breast cancer. Co-targeting CDK2 and CDK4/6 along with ET synergistically impairs cellular growth, induces cell cycle arrest and apoptosis, and delays progression in resistant cell models.
NPJ PRECISION ONCOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Shumeng Zhang, Qiaomai Xu, Wenjia Sun, Jianya Zhou, Jianying Zhou
Summary: The dysregulation of the cell cycle is a hallmark of cancer, and CDK4/6 inhibitors have shown great success in treating breast cancer. Evidence suggests that these inhibitors also have immunomodulatory effects, and their potential in combination with immune checkpoint inhibitors (ICIs) or CAR T-cell therapy is being explored to improve clinical outcomes.
BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER
(2023)
Review
Biochemistry & Molecular Biology
Jin Sun Lee, Hannah Hackbart, Xiaojiang Cui, Yuan Yuan
Summary: The emergence of CDK4/6 inhibitors has revolutionized the treatment of hormone receptor-positive breast cancer by demonstrating significant clinical benefits in terms of progression-free survival and overall survival. However, resistance to these inhibitors remains a challenge and understanding the underlying mechanisms is crucial for the development of novel therapeutic strategies. Translational research efforts, such as preclinical models and biomarker studies, provide valuable insights into resistance and may guide the identification of combination therapies.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
Xiuzhi Zhu, Li Chen, Binhao Huang, Xiaoguang Li, Liu Yang, Xin Hu, Yizhou Jiang, Zhimin Shao, Zhonghua Wang
Summary: The combination of PARPi olaparib and CDK4/6i palbociclib shows synergistic effects against BRCA(mut)/TNBC, especially in cells resistant to olaparib, by inhibiting HR repair, increasing DNA damage, and suppressing tumor growth.
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
(2021)
Review
Oncology
Ilenia Migliaccio, Angela Leo, Francesca Galardi, Cristina Guarducci, Giulio Maria Fusco, Matteo Benelli, Angelo Di Leo, Laura Biganzoli, Luca Malorni
Summary: This review discusses recent achievements in the development of circulating biomarkers in patients with metastatic breast cancer treated with CDK4/6 inhibitors and endocrine therapy. Circulating biomarkers have the potential advantages of recognizing patients who might not respond to treatment and monitoring treatment effects with a simple withdrawal of peripheral blood.Various circulating markers are currently being tested for their potential to predict response to CDK4/6 inhibitors treatment in patients with HR+/HER2- breast cancer.
Article
Oncology
Giulia Petroni, Aitziber Buque, Takahiro Yamazaki, Norma Bloy, Maurizio Di Liberto, Selina Chen-Kiang, Silvia C. Formenti, Lorenzo Galluzzi
Summary: Preclinical findings suggest that delivering radiotherapy before CDK4/6 inhibitors can achieve superior antineoplastic effects in breast cancer models, questioning the design of clinical trials administering CDK4/6 inhibitors before radiotherapy in women with ER+ breast cancer.
CLINICAL CANCER RESEARCH
(2021)
Review
Chemistry, Multidisciplinary
Xia-qing Xu, Xiao-hui Pan, Ting-ting Wang, Jian Wang, Bo Yang, Qiao-jun He, Ling Ding
Summary: Abnormal activation of cyclin-dependent kinases (CDKs) leads to aberrant cell proliferation, which is a key characteristic of tumors. Targeting the activity of CDKs is a promising therapeutic strategy, but resistance to CDK4/6 inhibitors has become a challenge. Resistance may be related to alterations in other molecular events that regulate the cell cycle progression.
ACTA PHARMACOLOGICA SINICA
(2021)
Review
Oncology
Mridula A. George, Sadaf Qureshi, Coral Omene, Deborah L. Toppmeyer, Shridar Ganesan
Summary: Targeted therapies such as CDK 4/6 inhibitors like palbociclib, ribociclib, and abemaciclib have improved the prognosis of metastatic HR positive breast cancer patients. While these three agents share overall similarities in CDK4/6 inhibition, there may be differences that explain unique clinical scenarios in which they are used.
FRONTIERS IN ONCOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Alessandra Ammazzalorso, Mariangela Agamennone, Barbara De Filippis, Marialuigia Fantacuzzi
Summary: Inhibition of cyclin dependent kinases 4 and 6 has shown efficacy in treating aromatase inhibitor resistant metastatic breast cancer. Recent advancements have led to the development of new selective CDK4/6 inhibitors with enhanced selectivity and treatment efficacy, aiming to reduce adverse effects.
Review
Oncology
Angeliki Andrikopoulou, Almog Shalit, Eleni Zografos, Konstantinos Koutsoukos, Anna-Maria Korakiti, Michalis Liontos, Meletios-Athanasios Dimopoulos, Flora Zagouri
Summary: MicroRNAs play a crucial role in sensitivity and resistance to CDK4/6 inhibitors, with some microRNAs serving as predictive biomarkers. MicroRNA-targeted therapy may potentially enhance sensitivity to CDK4/6 inhibition.
Review
Oncology
Ilenia Migliaccio, Martina Bonechi, Amelia McCartney, Cristina Guarducci, Matteo Benelli, Laura Biganzoli, Angelo Di Leo, Luca Malorni
Summary: CDK4/6 inhibitors in combination with endocrine therapy are the main treatment for metastatic breast cancer, but resistance can lead to treatment failure. Current approaches for patients who progress on CDK4/6 inhibitors include endocrine therapy alone, combination therapy, or chemotherapy. New agents are being developed based on potential mechanisms of acquired resistance.
CANCER TREATMENT REVIEWS
(2021)
Article
Biology
Viola Cogliati, Serena Capici, Francesca Fulvia Pepe, Pierluigi di Mauro, Francesca Riva, Federica Cicchiello, Claudia Maggioni, Nicoletta Cordani, Maria Grazia Cerrito, Marina Elena Cazzaniga
Summary: CDK4/6 inhibitors in combination with endocrine therapy are the best treatment option for advanced breast cancer. However, the optimal strategy after treatment failure remains unclear. This review analyzes resistance mechanisms and clinical trial results to provide a comprehensive overview.
Article
Biochemistry & Molecular Biology
Hongnan Mo, Xuefeng Liu, Yu Xue, Hongyan Chen, Shichao Guo, Zhangfu Li, Shuang Wang, Caiming Li, Jiashu Han, Ming Fu, Yongmei Song, Dan Li, Fei Ma
Summary: The innate resistance mechanism to CDK4/6 inhibitors is S6K1 amplification, which accounts for a certain proportion in breast cancer patients. Patients with S6K1 amplification have poor response to CDK4/6 inhibitors and may benefit from the combination of CDK4/6 and S6K1 antagonists.
Article
Medicine, General & Internal
Elisa Agostinetto, Veronique Debien, Guilherme Nader Marta, Matteo Lambertini, Martine Piccart-Gebhart, Evandro de Azambuja
Summary: The treatment landscape for HER2+ breast cancer is evolving rapidly, with CDK4/6 and PI3K inhibitors emerging as promising strategies to enhance patient outcomes. Data from preclinical and clinical studies are highlighting the potential of these agents in HER2+ disease and suggesting a potential shift in clinical practice.
EUROPEAN JOURNAL OF CLINICAL INVESTIGATION
(2021)
Article
Oncology
Xiaoqing Cheng, Yirui Sun, Maureen Highkin, Nagalaxmi Vemalapally, Xiaohua Jin, Brandon Zhou, Julie L. Prior, Ashley R. Tipton, Shunqiang Li, Anton Iliuk, Samuel Achilefu, Ian S. Hagemann, John R. Edwards, Ron Bose
Summary: In HER2-mutated breast cancer, PIK3CA mutation activates p21-CDK4/6-cyclin D1 signaling to drive resistance to HER2-targeted therapies, which can be overcome using CDK4/6 inhibitors.
Article
Pathology
Kaho Hiramatsu, Chiaki Matsuda, Katsuhiro Masago, Kazuhiro Toriyama, Eiichi Sasaki, Yasuko Fujita, Masataka Haneda, Hiromichi Ebi, Noriko Shibata, Waki Hosoda
Summary: In this study, the DNA integrity number (DIN) was evaluated in 166 tumor tissue samples, and a DIN cutoff of 2.5 was identified as a reliable indicator for successful analysis. Additionally, a new metric called peak/base ratio was introduced, which exhibited higher predictive accuracy than the DIN.
AMERICAN JOURNAL OF CLINICAL PATHOLOGY
(2023)
Article
Oncology
Akimitsu Maeda, Hitoshi Ando, Kei Irie, Naoya Hashimoto, Jun-ichi Morishige, Shoji Fukushima, Hiromichi Ebi, Kosaku Uchida, Hiroji Iwata, Masataka Sawaki
Summary: The study evaluated the effects of ABCB1 and ABCG2 gene polymorphisms on the pharmacokinetics of abemaciclib metabolites M2, M20, and M18. The results suggest that the ABCB1 2677G>T/A polymorphism may influence tolerance to abemaciclib in breast cancer patients by affecting the pharmacokinetics of the drug and its active metabolites.
ANTICANCER RESEARCH
(2023)
Article
Cardiac & Cardiovascular Systems
Karen L. Kelly, Peter T. Lin, Cristina Basso, Melanie Bois, L. Maximilian Buja, Stephen D. Cohle, Giulia d'Amati, Emily Duncanson, John T. Fallon, Dennis Firchau, Gregory Fishbein, Carla Giordano, Charles Leduc, Silvio H. Litovsky, Shannon Mackey-Bojack, Joseph J. Maleszewski, Katarzyna Michaud, Robert F. Padera, Stavroula A. Papadodima, Sarah Parsons, Stanley J. Radio, Stefania Rizzo, Susan J. Roe, Maria Romero, Mary N. Sheppard, James R. Stone, Carmela D. Tan, Gaetano Thiene, Allard C. van der Wal, John P. Veinot
Summary: Sudden cardiac death is an unexpected death caused by a cardiac condition, accounting for approximately 15-20% of all deaths. It commonly occurs in older adults with acquired heart disease but can also happen in young individuals due to genetic transmission. Investigation of these deaths is crucial due to the potential impact on other family members and the lack of consistent guidelines for cardiac examination in these cases.
CARDIOVASCULAR PATHOLOGY
(2023)
Article
Cell Biology
Badri Krishnan, Ioannis Sanidas, Nicholas J. Dyson
Summary: This study found that active forms of RB can cause widespread changes in nuclear architecture, which are not correlated with cell cycle arrest or repression of the E2F transcriptional program. Instead, these changes appear later and are associated with autophagy or senescence markers in IMR-90 cells. This perspective discusses the relative timing of these RB-induced events, the mechanisms underlying RB-induced chromatin dispersion, and the potential connection between dispersion and cell cycle exit.
Article
Medicine, General & Internal
Tanayott Thaweethai, Sarah E. Jolley, Elizabeth W. Karlson, Emily B. Levitan, Bruce Levy, Grace A. McComsey, Lisa McCorkell, Girish N. Nadkarni, Sairam Parthasarathy, Upinder Singh, Tiffany A. Walker, Caitlin A. Selvaggi, Daniel J. Shinnick, Carolin C. M. Schulte, Rachel Atchley-Challenner, Leora I. Horwitz, Andrea S. Foulkes
Summary: SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, known as postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID. This study developed a definition of PASC based on self-reported symptoms and described the frequencies of PASC across cohorts, vaccination status, and number of infections.
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
(2023)
Article
Cardiac & Cardiovascular Systems
James P. Pirruccello, Joel T. Ramo, Seung Hoan Choi, Mark D. Chaffin, Shinwan Kany, Mahan Nekoui, Elizabeth L. Chou, Sean J. Jurgens, Samuel F. Friedman, Dejan Juric, James R. Stone, Puneet Batra, Kenney Ng, Anthony A. Philippakis, Mark E. Lindsay, Patrick T. Ellinor
Summary: Genetic determinants of aortic function influence the risk for stroke and coronary artery disease, and may lead to novel targets for medical intervention.
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
(2023)
Editorial Material
Oncology
Hiromichi Ebi
JOURNAL OF THORACIC ONCOLOGY
(2023)
Article
Rheumatology
Guy Katz, Sandeep H. Hedgire, James R. Stone, Sebastian Perez-Espina, Ana Fernandes, Cory A. Perugino, Zachary S. Wallace, John H. Stone
Summary: IgG4-related disease is a systemic autoimmune fibroinflammatory disease that can affect multiple organ systems. Coronary artery involvement is an important manifestation of IgG4-RD, causing potential complications such as coronary artery aneurysms, myocardial infarction, and ischemic cardiomyopathy.
SEMINARS IN ARTHRITIS AND RHEUMATISM
(2023)
Review
Oncology
Rachel Occhiogrosso Abelman, Bogang Wu, Laura M. Spring, Leif W. Ellisen, Aditya Bardia
Summary: Antibody-drug conjugates (ADCs) are a promising class of therapies that deliver targeted treatment with fewer side effects. Despite their success, resistance to ADCs in breast cancer and other malignancies remains a challenge. This paper reviews the literature on the mechanisms of resistance to ADCs and discusses potential strategies to overcome them.
Article
Oncology
Neelima Vidula, Andrzej Niemierko, Katherine Hesler, Lianne Ryan, Beverly Moy, Steven Isakoff, Leif Ellisen, Dejan Juric, Aditya Bardia
Summary: We compared the cell-free DNA (cfDNA) results at the time of diagnosis of metastatic breast cancer (MBC) in patients who developed brain metastases (BM) with those who did not, in order to identify genomic predictors of BM. Among patients who underwent cfDNA testing at MBC diagnosis using Guardant360 (R) technology, we found that 21% of them developed BM. Comparing BM patients with non-BM patients, we observed a higher prevalence of specific gene mutations such as BRCA2, APC, CDKN2A, and SMAD4 in the former group. This genomic pattern had a high negative predictive value (85%) and specificity (93%) in excluding BM development.
Article
Oncology
Yuta Adachi, Ryo Kimura, Kentaro Hirade, Shogo Yanase, Yuki Nishioka, Natsumi Kasuga, Rui Yamaguchi, Hiromichi Ebi
Summary: This study reveals that inhibition of MAPK signaling leads to the induction of epithelial-to-mesenchymal transition by promoting the mis-localization of Scribble protein. This mis-localization suppresses Hippo-YAP signaling and triggers YAP nuclear translocation. Additionally, the study identifies MRAS as a direct target of YAP and demonstrates its involvement in feedback activation of MAPK signaling and adaptive resistance to KRAS G12C inhibitors.
Article
Cardiac & Cardiovascular Systems
Vidhya Nair, Gregory A. Fishbein, Robert Padera, Michael A. Seidman, Mathieu Castonguay, Charles Leduc, Carmela D. Tan, E. Rene Rodriguez, Joseph J. Maleszewski, Dylan Miller, Maria Romero, Jon Lomasney, Giulia d'Amati, Monica De Gaspari, Stefania Rizzo, Annalisa Angelini, Cristina Basso, Silvio Litovsky, Louis Maximilian Buja, James R. Stone, John P. Veinot
Summary: Giant cell arteritis (GCA) is the most common systemic vasculitis in adults in Europe and North America, and temporal artery biopsy (TAB) remains the gold standard for diagnosis. To address the lack of uniformity in processing and interpretation of TAB specimens, the Society for Cardiovascular Pathology has established consensus guidelines based on existing literature. The guidelines also discuss differential diagnoses and noninflammatory changes of the temporal artery.
CARDIOVASCULAR PATHOLOGY
(2023)
Editorial Material
Cardiac & Cardiovascular Systems
James R. Stone
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
(2023)
Article
Immunology
Aram J. Krauson, Faye Victoria C. Casimero, Zakir Siddiquee, James R. Stone
Summary: At the start of the COVID-19 pandemic, the BNT162b2 (BioNTech-Pfizer) and mRNA-1273 (Moderna) mRNA vaccines were designed and produced rapidly. This study found that both vaccines can persist in human tissues for up to 30 days after vaccination. Additionally, the study detected the vaccine in the myocardium of deceased patients who had been vaccinated within 30 days of death.
Article
Medicine, General & Internal
Tanayott R. Thaweethai, Sarah E. Jolley, Elizabeth Karlson, Emily M. Levitan, Bruce Levy, Grace McComsey, Lisa S. McCorkell, Girish D. Nadkarni, Sairam E. Parthasarathy, Upinder J. Singh, Tiffany Walker, Caitlin W. Selvaggi, Daniel Shinnick, Carolin C. M. P. Schulte, Rachel M. Atchley-Challenner, Leora Horwitz, Andrea Foulkes
Summary: This study aims to develop a definition of postacute sequelae of SARS-CoV-2 infection (PASC) using self-reported symptoms and analyze the frequencies of PASC across different cohorts, vaccination status, and number of infections. The results show that PASC is associated with various symptoms and around 10% of participants were PASC positive at 6 months after infection.
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
(2023)