Despite the success of antiestrogens in extending overall survival of patients with estrogen receptor positive (ER+) breast tumors, resistance to these therapies is prevalent. ER+ tumors that progress on antiestrogens are treated with antiestrogens and CDK4/6 inhibitors. However, 20% of these tumors never respond to CDK4/6 inhibitors due to intrinsic resistance. Here, we used endocrine sensitive ER+ MCF7 and T47D breast cancer cells to generate long-term estrogen deprived (LTED) endocrine resistant cells that are intrinsically resistant to CDK4/6 inhibitors. Since treatment with antiestrogens arrests cells in the G1 phase of the cell cycle, we hypothesized that a defective G1 checkpoint allows resistant cells to escape this arrest but increases their dependency on G2 checkpoint for DNA repair and growth, and hence, targeting the G2 checkpoint will induce cell death. Indeed, inhibition of WEE1, a crucial G2 checkpoint regulator, with AZD1775 (Adavosertib), significantly decreased cell proliferation and increased G2/M arrest, apoptosis and gamma-H2AX levels (a marker for DNA double stranded breaks) in resistant cells compared with sensitive cells. Thus, targeting WEE1 is a promising anti-cancer therapeutic strategy in standard therapy resistant ER+ breast cancer.
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http://dx.doi.org/10.3389/fonc.2021.681530 | DOI Listing |
Gynecol Oncol Rep
February 2025
Department of Obstetrics and Gynaecology, Faculty of Medicine, King Abdulaziz University, Rabigh, Saudi Arabia.
Endometrial stromal tumors (ESTs) are uncommon mesenchymal tumors of the reproductive system associated with heterogeneous histomolecular features. According to the World Health Organization (WHO), ESTs are classified into benign endometrial stromal nodules (BESN) and endometrial stromal sarcomas (ESSs), which are further divided into low-grade and high-grade subtypes. High-grade ESS is frequently associated with YWHAE-NUTM2 gene fusions, while a newly recognized subtype with BCOR rearrangements, including fusions, alterations, and internal tandem duplications (ITDs), has recently been incorporated into the molecular classification of ESS.
View Article and Find Full Text PDFBreast Cancer Res
January 2025
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
Background: CDK4/6 inhibitors have significantly improved the survival of patients with HR-positive/HER2-negative breast cancer, becoming a first-line treatment option. However, the development of resistance to these inhibitors is inevitable. To address this challenge, novel strategies are required to overcome resistance, necessitating a deeper understanding of its mechanisms.
View Article and Find Full Text PDFESMO Open
January 2025
Department of Internal Medicine, Division of Medical Oncology, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address:
Background: Disruption of cyclin D-dependent kinases (CDKs), particularly CDK4/6, drives cancer cell proliferation via abnormal protein phosphorylation. This open-label, single-arm, phase Ib/II trial evaluated the efficacy of the CDK4/6 inhibitor, abemaciclib, combined with paclitaxel against CDK4/6-activated tumors.
Patients And Methods: Patients with locally advanced or metastatic solid tumors with CDK4/6 pathway aberrations were included.
Cardiooncology
January 2025
Thalheimer Center for Cardio-Oncology, Division of Cardiology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
Background: Cardiovascular (CV) comorbidities and concurrent medications with risk of heart rate-corrected QT interval (QTc) prolongation can impact treatment decisions and safety discussions for patients with breast cancer. However, limited data are available regarding their prevalence in patients with HR + /HER2- metastatic breast cancer (mBC). We evaluated the prevalence of CV comorbidities, the use of concurrent medications with risk of QTc prolongation, and treatment patterns in patients with newly diagnosed HR + /HER2 - mBC.
View Article and Find Full Text PDFNPJ Breast Cancer
January 2025
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Endocrine therapy with CDK4/6 inhibitors is standard for estrogen receptor-positive, HER2-negative metastatic breast cancer (ER+/HER2- MBC), yet clinical resistance develops. Previously, we demonstrated that low doses of palbociclib activate autophagy, reversing initial G1 cell cycle arrest, while high concentrations induce off-target senescence. The autophagy inhibitor hydroxychloroquine (HCQ) induced on-target senescence at lower palbociclib doses.
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