Cyclin-dependent kinase 2 (CDK2) inhibitors and others novel CDK inhibitors (CDKi) in breast cancer: clinical trials, current impact, and future directions

Critical Reviews in Oncology/Hematology, Journal Year: 2024, Volume and Issue: 196, P. 104324 - 104324

Published: March 8, 2024

Aberrant cyclin-dependent kinase 2 (CDK2) activation has been identified as a main resistance mechanism to CDK4/6 inhibition in hormone-receptor positive (HR+) breast cancer. Additionally, consistent preclinical evidence states its crucial role MYC and CCNE1 overexpressed cancer survival, such triple-negative cancers (TNBC), thus representing an appealing relatively unexplored target treatment opportunity. Despite emerging initial results of novel CDK2 inhibitors (CDK2i) activity, comprehensive outcomes collection is currently absent from the scientific literature. We aim provide overview ongoing clinical trials involving CDK2i context metastatic (mBC), either monotherapy or combination with other agents. The review extends beyond encompass CDK4 inhibitors, combined CDK2/4/6 well-known pan-CDK including those specifically directed at CDK2. Delving into results, we critically appraise observed efficacy offer valuable insights their potential impact future applications.

Language: Английский

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A deep learning model of tumor cell architecture elucidates response and resistance to CDK4/6 inhibitors

Nature Cancer, Journal Year: 2024, Volume and Issue: 5(7), P. 996 - 1009

Published: March 5, 2024

Abstract Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have revolutionized breast cancer therapy. However, <50% of patients an objective response, nearly all develop resistance during To elucidate the underlying mechanisms, we constructed interpretable deep learning model response to palbociclib, a CDK4/6i, based on reference map multiprotein assemblies in cancer. The identifies eight core that integrate rare common alterations across 90 genes stratify palbociclib-sensitive versus palbociclib-resistant cell lines. Predictions translate patient-derived xenografts, whereas single-gene biomarkers do not. Most predictive can be shown by CRISPR–Cas9 genetic disruption regulate CDK4/6i response. Validated relate cell-cycle control, growth factor signaling histone regulatory complex show promotes S-phase entry through activation modifiers KAT6A TBL1XR1 transcription RUNX1. This study enables integrated assessment how tumor’s profile modulates resistance.

Language: Английский

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Molecular mechanisms and therapeutic strategies in overcoming chemotherapy resistance in cancer

Molecular Biomedicine, Journal Year: 2025, Volume and Issue: 6(1)

Published: Jan. 6, 2025

Cancer remains a leading cause of mortality globally and major health burden, with chemotherapy often serving as the primary therapeutic option for patients advanced-stage disease, partially compensating limitations non-curative treatments. However, emergence resistance significantly limits its efficacy, posing clinical challenge. Moreover, heterogeneity mechanisms across cancer types complicates development universally effective diagnostic approaches. Understanding molecular chemoresistance identifying strategies to overcome it are current research focal points. This review provides comprehensive analysis key underlying resistance, including drug efflux, enhanced DNA damage repair (DDR), apoptosis evasion, epigenetic modifications, altered intracellular metabolism, role stem cells (CSCs). We also examine specific causes in highlight various targets involved resistance. Finally, we discuss aiming at overcoming such combination therapies, targeted treatments, novel delivery systems, while proposing future directions this evolving field. By addressing these barriers, lays foundation more therapies aimed mitigating

Language: Английский

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Oncogenic signals prime cancer cells for toxic cell overgrowth during a G1 cell cycle arrest

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(22), P. 4047 - 4061.e6

Published: Nov. 1, 2023

CDK4/6 inhibitors are remarkable anti-cancer drugs that can arrest tumor cells in G1 and induce their senescence while causing only relatively mild toxicities healthy tissues. How they achieve this mechanistically is unclear. We show here specifically vulnerable to inhibition because during the arrest, oncogenic signals drive toxic cell overgrowth. This overgrowth causes permanent cycle withdrawal by either preventing progression from or inducing genotoxic damage subsequent S-phase mitosis. Inhibiting reverting converge onto mTOR rescue excessive growth, DNA damage, exit cancer cells. Conversely, non-transformed these phenotypes sensitize inhibition. Together, demonstrates growth a synthetic lethal combination exploited tumor-specific toxicity.

Language: Английский

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Emerging systemic therapy options beyond CDK4/6 inhibitors for hormone receptor-positive HER2-negative advanced breast cancer

npj Breast Cancer, Journal Year: 2023, Volume and Issue: 9(1)

Published: Sept. 8, 2023

Abstract Endocrine therapy (ET) with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is currently the standard first-line treatment for most patients hormone receptor (HR) positive, human epidermal growth factor (HER2) negative advanced breast cancer. However, resistance to ET and CDK4/6i inevitably ensues. The optimal post-progression regimens their sequencing continue evolve in rapidly changing landscape. In this review, we summarize mechanisms of CDK4/6i, which can be broadly classified as alterations affecting cell cycle mediators activation alternative signaling pathways. Recent clinical trials have been directed at targets pathways implicated, including estrogen androgen receptors, PI3K/AKT/mTOR MAPK pathways, tyrosine receptors such FGFR HER2, homologous recombination repair pathway, other components death. We describe findings from these using small molecule inhibitors, antibody–drug conjugates immunotherapy, providing insights into how novel strategies may circumvent resistance, discuss some not translated benefit. challenges posed by tumor heterogeneity, adaptive rewiring dose-limiting toxicities underscore need elucidate latest biology each patient, develop treatments improved therapeutic index era precision medicine.

Language: Английский

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The dilemma of selecting a first line CDK4/6 inhibitor for hormone receptor-positive/HER2-negative metastatic breast cancer

npj Breast Cancer, Journal Year: 2023, Volume and Issue: 9(1)

Published: March 22, 2023

The combination of an endocrine agent with a CDK4/6 inhibitor is the standard care in first-line setting for patients hormone receptor-positive, HER2-negative metastatic breast cancer. Randomized trials have demonstrated similar and significant improvements progression-free survival using three available inhibitors led to regulatory approval. However, mature overall data now suggest potential differences among various agents, suggesting evolution selection preferences.

Language: Английский

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AKT/mTOR signaling modulates resistance to endocrine therapy and CDK4/6 inhibition in metastatic breast cancers

npj Precision Oncology, Journal Year: 2023, Volume and Issue: 7(1)

Published: Feb. 16, 2023

Endocrine therapy (ET) in combination with CDK4/6 inhibition is routinely used as first-line treatment for HR+/HER2- metastatic breast cancer (MBC) patients. However, 30-40% of patients quickly develop disease progression. In this open-label multicenter clinical trial, we utilized a hypothesis-driven protein/phosphoprotein-based approach to identify predictive markers response ET plus pre-treatment tissue biopsies. Pathway-centered signaling profiles were generated from microdissected tumor epithelia and surrounding stroma/immune cells using the reverse phase protein microarray. Phosphorylation levels downstream substrates Rb (S780) FoxM1 (T600) higher progressive (PD) compared responders (p = 0.02). Systemic PI3K/AKT/mTOR activation was detected PD. This not explained by underpinning genomic alterations alone. As number FDA-approved targeted compounds increases, functional protein-based analyses may become critical component prediction selection MBC

Language: Английский

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Design, synthesis, antineoplastic activity of new pyrazolo[3,4-d]pyrimidine derivatives as dual CDK2/GSK3β kinase inhibitors; molecular docking study, and ADME prediction

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 150, P. 107566 - 107566

Published: June 15, 2024

Language: Английский

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Mechanisms of sensitivity and resistance to CDK4/CDK6 inhibitors in hormone receptor-positive breast cancer treatment

Drug Resistance Updates, Journal Year: 2024, Volume and Issue: 76, P. 101103 - 101103

Published: June 25, 2024

Cell cycle dysregulation is a hallmark of cancer that promotes eccessive cell division. Cyclin-dependent kinase 4 (CDK4) and cyclin-dependent 6 (CDK6) are key molecules in the G1-to-S phase transition crucial for onset, survival, progression breast (BC). Small-molecule CDK4/CDK6 inhibitors (CDK4/6i) block phosphorylation tumor suppressor Rb thus restrain susceptible BC cells G1 phase. Three CDK4/6i approved first-line treatment patients with advanced/metastatic hormone receptor-positive (HR

Language: Английский

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Therapeutic benefits of maintaining CDK4/6 inhibitors and incorporating CDK2 inhibitors beyond progression in breast cancer

Published: Jan. 28, 2025

The combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy has revolutionized treatment for hormone receptor-positive (HR+) metastatic breast cancer. However, the emergence resistance in most patients often leads to discontinuation with no consensus on effective second-line therapies. therapeutic benefits maintaining CDK4/6i or incorporating CDK2 (CDK2i) after disease progression remain unclear. Here, we demonstrate that sustained therapy, either alone combined CDK2i, significantly suppresses growth drug-resistant HR + Continued induces a non-canonical pathway retinoblastoma protein (Rb) inactivation via post-translational degradation, resulting diminished E2F activity delayed G1 progression. Importantly, our data highlight CDK2i should be effectively suppress overcome resistance. We also identify cyclin E overexpression as key driver inhibition. These findings provide crucial insights into overcoming cancer, supporting continued use strategic incorporation improve outcomes.

Language: Английский

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