Review
Pharmacology & Pharmacy
C. Louwrens Braal, Elisabeth M. Jongbloed, Saskia M. Wilting, Ron H. J. Mathijssen, Stijn L. W. Koolen, Agnes Jager
Summary: CDK 4/6 inhibitors are a new class of drugs that interrupt proliferation of malignant cells by inhibiting progression through the cell cycle. This article reviews the clinical pharmacokinetic and pharmacodynamic profiles of these inhibitors and discusses important future directions for their clinical applicability.
Article
Chemistry, Analytical
Katharina Habler, Anne -Sophie Kalla, Michael Rychlik, Michael Vogeser, Daniel Teupser
Summary: A semi-automated LC-MS/MS method was developed for the simultaneous quantification of abemaciclib, its active metabolites, palbociclib, and ribociclib in human serum. The method was validated according to FDA guidance and showed good accuracy and precision. This method has the potential for routine analysis to improve personalized therapy, patient safety, and treatment success.
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
(2023)
Article
Multidisciplinary Sciences
Carla L. Alves, Sidse Ehmsen, Mikkel G. Terp, Neil Portman, Martina Tuttolomondo, Odd L. Gammelgaard, Monique F. Hundebol, Kamila Kaminska, Lene E. Johansen, Martin Bak, Gabriella Honeth, Ana Bosch, Elgene Lim, Henrik J. Ditzel
Summary: The study demonstrates that triple inhibition with fulvestrant, CDK4/6i, and AKT inhibitor durably impairs growth of breast cancer cells, prevents progression, and reduces metastasis. Switching from combined fulvestrant and CDK4/6i to dual combination with AKTi and fulvestrant does not prevent tumor progression after resistance. High phospho-AKT levels in metastasis correlate with shorter progression-free survival in breast cancer patients treated with a combination of CDK4/6i and endocrine therapy.
NATURE COMMUNICATIONS
(2021)
Article
Medical Laboratory Technology
Sarah M. M. Burke, Mustafa K. L. Kamal, Andrew K. L. Goey
Summary: A sensitive liquid chromatography coupled with tandem mass spectrometry method was developed to measure the concentration of CDK4/6 inhibitors and the major active metabolite M2 of abemaciclib in human plasma. The method was validated according to the criteria of the Food and Drug Administration, and can accurately and precisely measure the concentrations of all analytes, making it suitable for therapeutic drug monitoring and clinical pharmacokinetic studies.
THERAPEUTIC DRUG MONITORING
(2023)
Article
Chemistry, Medicinal
Huifang Shan, Xinyu Ma, Guoyi Yan, Meng Luo, Xinxin Zhong, Suke Lan, Jie Yang, Yuanyuan Liu, Chunlan Pu, Yu Tong, Rui Li
Summary: A series of covalent CDK4/6 inhibitors were designed and synthesized, with compound C-13 showing potent anticancer activity in vitro and significant tumor growth inhibition in a mouse model.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Pharmacology & Pharmacy
Zhimin Zhu, Qiongni Zhu
Summary: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are crucial in cancer treatment, especially breast cancer, and understanding their differences in mechanism of action and resistance is vital. This study aimed to summarize the metabolic and transport variations as well as resistance differences among the FDA-approved CDK4/6 inhibitors: Abemaciclib, Palbociclib, and Ribociclib. Variations in metabolism, preclinical pharmacology, pharmacokinetics, safety, and efficacy were found among the inhibitors. Genetic mutations and drug tolerance may influence CDK4/6 resistance mechanisms. Further exploration and research are needed due to the remaining unknowns and differences in resistance mechanisms among the three drugs.
FRONTIERS IN PHARMACOLOGY
(2023)
Review
Oncology
Maxwell R. Lloyd, Laura M. Spring, Aditya Bardia, Seth A. Wander
Summary: CDK4/6 inhibitors have become the standard of care for patients with hormone receptor-positive advanced breast cancer. Research efforts have identified common resistance drivers and precision-guided therapeutic strategies are under development.
CLINICAL CANCER RESEARCH
(2022)
Article
Multidisciplinary Sciences
Marta Palafox, Laia Monserrat, Meritxell Bellet, Guillermo Villacampa, Abel Gonzalez-Perez, Mafalda Oliveira, Fara Braso-Maristany, Nusaibah Ibrahimi, Srinivasaraghavan Kannan, Leonardo Mina, Maria Teresa Herrera-Abreu, Andreu Odena, Monica Sanchez-Guixe, Marta Capelan, Analia Azaro, Alejandra Bruna, Olga Rodriguez, Marta Guzman, Judit Grueso, Cristina Viaplana, Javier Hernandez, Faye Su, Kui Lin, Robert B. Clarke, Carlos Caldas, Joaquin Arribas, Stefan Michiels, Alicia Garcia-Sanz, Nicholas C. Turner, Aleix Prat, Paolo Nuciforo, Rodrigo Dienstmann, Chandra S. Verma, Nuria Lopez-Bigas, Maurizio Scaltriti, Monica Arnedos, Cristina Saura, Violeta Serra
Summary: CDK4/6 inhibitors combined with endocrine therapy show higher antitumor activity in the treatment of estrogen receptor-positive breast cancer. Overexpression of p16 is associated with reduced effectiveness of CDK4/6 inhibitors, while heterozygous RB1 loss is a biomarker of acquired resistance and poor clinical outcome. Combination of CDK4/6 inhibitor ribociclib with PI3K inhibitor alpelisib demonstrates antitumor activity regardless of specific mutations, even without endocrine therapy.
NATURE COMMUNICATIONS
(2022)
Review
Biochemistry & Molecular Biology
Ioana-Miruna Stanciu, Andreea Ioana Parosanu, Cornelia Nitipir
Summary: Cyclin-dependent kinase 4 and 6 inhibitors have revolutionized the treatment of HR+ and HER2- breast cancer, but their use is associated with adverse events. This review provides the latest summary on the safety profile of these inhibitors.
Article
Pharmacology & Pharmacy
Jing Ji, Wenwen Liu, Yuxin Xu, Zhou Xu, Mingxiao Lv, Jing Feng, Jinyu Lv, Xingbei He, Zhen Zhang, Mengru Xie, Aixin Jing, Xiujun Wang, Jinming Ma, Bin Liu
Summary: A novel derivative of Ribociclib, WXJ-202, was designed and synthesized to target CDK4/6 in breast cancer cells. WXJ-202 exhibited inhibitory effects on cell proliferation, colony formation, migration, and invasion, as well as induced apoptosis and cell cycle arrest. The expression levels of proteins related to the CDK4/6-Rb-E2F pathway were decreased by WXJ-202. Moreover, WXJ-202 showed significant anti-tumor activity in transplantation tumor models.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Monica Cejuela, Ana Gil-Torralvo, M. Angeles Castilla, M. Angeles Dominguez-Cejudo, Alejandro Falcon, Marta Benavent, Sonia Molina-Pinelo, Manuel Ruiz-Borrego, Javier Salvador Bofill
Summary: By the end of 2020, breast cancer became the most prevalent neoplasia worldwide. Endocrine therapy combined with CDK4/6 inhibitors has become the gold standard for ER-positive and HER-2-negative metastatic breast cancer. A comparative efficacy analysis of the three CDK4/6 inhibitors, abemaciclib, palbociclib, and ribociclib, using real-world data found that abemaciclib showed significant benefits in terms of progression-free survival in endocrine-resistant patients and those without visceral involvement.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cell Biology
Sijie Wang, Yuncheng Bei, Qiang Tian, Jian He, Rui Wang, Qiuping Wang, Luchen Sun, Jiangqiong Ke, Congying Xie, Pingping Shen
Summary: This study revealed an adaptive resistance mechanism in ER+ breast cancer cells to palbociclib, involving activation of an alternative pathway independent of CDK4/6-RB signaling. Continuous treatment with palbociclib induced cellular senescence and promoted stemness in ER+ breast cancer cells, resulting in increased chemoresistance and tumor-initiating potential. PFKFB4 was identified as a key player in stemness transformation and drug resistance. Metabolomic profiling showed that PFKFB4 reprogrammed glucose metabolism and enhanced glycolysis to promote cell stemness. Lowering PFKFB4 levels improved drug sensitivity and overcame chemoresistance during palbociclib treatment in ER+ breast cancer.
CELL PROLIFERATION
(2023)
Article
Oncology
Severine Isabelle Gharbi, Laura A. Pelletier, Alfonso Espada, Jesus Gutierrez, Sonia Maria Gutierrez Sanfeliciano, Charles T. Rauch, Maria Patricia Ganado, Carmen Baquero, Elisabet Zapatero, Aiping Zhang, Jordi Benach, Anna-Maria Russell, Leticia Cano, Sandra Gomez, Howard Broughton, Nicholas Pulliam, Carmen Maria Perez, Raquel Torres, Marjoke F. Debets, Alfonso de Dios, Oscar Puig, Mark T. Hilgers, Maria Jose Lallena
Summary: This study provides insights into the mechanism of CDK4/6 inhibitors, showing that CDK4/6i can stabilize the mature CDK4-cyclin D complex and selectively displace p21. Prolonged binding of abemaciclib to CDK4 leads to potent cell cycle inhibition in breast cancer cell lines and prevents rebound activation of downstream signaling.
Article
Oncology
Mohammadhadi Khorrami, Vidya Sakar Viswanathan, Priyanka Reddy, Nathaniel Braman, Siddharth Kunte, Amit Gupta, Jame Abraham, Alberto J. Montero, Anant Madabhushi
Summary: Imaging texture biomarkers before and after CDK4/6i therapy can predict early response and overall survival in MBC patients with liver metastases. Radiomic features can predict a lack of response earlier than standard anatomic/RECIST 1.1 assessment, highlighting the need for further study and clinical validation.
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)
Article
Biochemistry & Molecular Biology
Xi Chen, Jin-Gyoung Jung, Ayesha N. Shajahan-Haq, Robert Clarke, Ie-Ming Shih, Yue Wang, Luca Magnani, Tian-Li Wang, Jianhua Xuan
NUCLEIC ACIDS RESEARCH
(2016)
Article
Oncology
Peter C. Hart, Bianca A. Ratti, Mao Mao, Kristine Ansenberger-Fricano, Ayesha N. Shajahan-Haq, Angela L. Tyner, Richard D. Minshall, Marcelo G. Bonini
Article
Biochemical Research Methods
Xi Chen, Xu Shi, Leena Hilakivi-Clarke, Ayesha N. Shajahan-Haq, Robert Clarke, Jianhua Xuan
Editorial Material
Oncology
Tenley C. Archer, Elana J. Fertig, Sara J. C. Gosline, Marc Hafner, Shannon K. Hughes, Brian A. Joughin, Aaron S. Meyer, Stephen R. Piccolo, Ayesha N. Shajahan-Haq
Article
Cell Biology
Adriana M. Zimnicka, Yawer S. Husain, Ayesha N. Shajahan, Maria Sverdlov, Oleg Chaga, Zhenlong Chen, Peter T. Toth, Jennifer Klomp, Andrei V. Karginov, Chinnaswamy Tiruppathi, Asrar B. Malik, Richard D. Minshall
MOLECULAR BIOLOGY OF THE CELL
(2016)
Article
Oncology
Ayesha N. Shajahan-Haq, Simina M. Boca, Lu Jin, Krithika Bhuvaneshwar, Yuriy Gusev, Amrita K. Cheema, Diane D. Demas, Kristopher S. Raghavan, Ryan Michalek, Subha Madhavan, Robert Clarke
Review
Pharmacology & Pharmacy
Filipa Lynce, Ayesha N. Shajahan-Haq, Sandra M. Swain
PHARMACOLOGY & THERAPEUTICS
(2018)
Review
Oncology
Jeannine M. Salamone, Wanda Lucas, Shelley B. Brundage, Jamie N. Holloway, Sherri M. Stahl, Nora E. Carbine, Margery London, Naomi Greenwood, Rosa Goyes, Deborah Charles Chisholm, Erin Price, Roberta Carlin, Susan Winarsky, Kirsten B. Baker, Julia Maues, Ayesha N. Shajahan-Haq
Article
Oncology
Diane M. Demas, Susan Demo, Yassi Fallah, Robert Clarke, Kenneth P. Nephew, Sandra Althouse, George Sandusky, Wei He, Ayesha N. Shajahan-Haq
FRONTIERS IN ONCOLOGY
(2019)
Article
Multidisciplinary Sciences
Wei He, Diane M. Demas, Isabel P. Conde, Ayesha N. Shajahan-Haq, William T. Baumann
JOURNAL OF THE ROYAL SOCIETY INTERFACE
(2020)
Article
Oncology
Suzanne Bakewell, Isabel Conde, Yassi Fallah, Mathew McCoy, Lu Jin, Ayesha N. Shajahan-Haq
Article
Biochemical Research Methods
Sepeedah Soltanian-Zadeh, Kruthika Kikkeri, Ayesha N. Shajahan-Haq, Jeannine Strobl, Robert Clarke, Masoud Agah
Review
Biochemistry & Molecular Biology
Yassi Fallah, Janetta Brundage, Paul Allegakoen, Ayesha N. Shajahan-Haq