CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence

Molecular Cell, Год журнала: 2023, Номер 83(22), С. 4062 - 4077.e5

Опубликована: Ноя. 1, 2023

Abnormal increases in cell size are associated with senescence and cycle exit. The mechanisms by which overgrowth primes cells to withdraw from the remain unknown. We address this question using CDK4/6 inhibitors, arrest G0/G1 licensed treat advanced HR+/HER2- breast cancer. demonstrate that CDK4/6-inhibited overgrow during G0/G1, causing p38/p53/p21-dependent withdrawal. Cell withdrawal is triggered biphasic p21 induction. first wave caused osmotic stress, leading p38- size-dependent accumulation of p21. inhibitor washout results some entering S-phase. Overgrown experience replication resulting a second promotes G2 or subsequent G1. propose levels integrate signals overgrowth-triggered stresses determine fate. This model explains how hypertrophy can drive why inhibitors have long-lasting effects patients.

Язык: Английский

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Regulation of cellular senescence in tumor progression and therapeutic targeting: mechanisms and pathways

Molecular Cancer, Год журнала: 2025, Номер 24(1)

Опубликована: Апрель 2, 2025

Cellular senescence, a stable state of cell cycle arrest induced by various stressors or genomic damage, is recognized as hallmark cancer. It exerts context-dependent dual role in cancer initiation and progression, functioning tumor suppressor promoter. The complexity senescence arises from its mechanistic diversity, potential reversibility, heterogeneity. A key mediator these effects the senescence-associated secretory phenotype (SASP), repertoire bioactive molecules that influence microenvironment (TME) remodeling, modulate behavior, contribute to therapeutic resistance. Given intricate biology, presents both challenges opportunities for intervention. Strategies targeting pathways, including senescence-inducing therapies senolytic approaches, offer promising avenues treatment. This review provides comprehensive analysis regulatory mechanisms governing cellular tumors. We also discuss emerging strategies highlighting novel opportunities. deeper understanding processes essential developing precision improving clinical outcomes.

Язык: Английский

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

Molecular Cell, Год журнала: 2023, Номер 83(22), С. 4047 - 4061.e6

Опубликована: Ноя. 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.

Язык: Английский

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Active growth signaling promotes senescence and cancer cell sensitivity to CDK7 inhibition

Molecular Cell, Год журнала: 2023, Номер 83(22), С. 4078 - 4092.e6

Опубликована: Ноя. 1, 2023

Tumor growth is driven by continued cellular and proliferation. Cyclin-dependent kinase 7's (CDK7) role in activating mitotic CDKs global gene expression makes it therefore an attractive target for cancer therapies. However, what cells particularly sensitive to CDK7 inhibition (CDK7i) remains unclear.Here, we address this question. We show that CDK7i, samuraciclib, induces a permanent cell-cycle exit, known as senescence, without promoting DNA damage signaling or cell death. A chemogenetic genome-wide CRISPR knockout screen identified active mTOR (mammalian of rapamycin) promotes samuraciclib-induced senescence. decreases samuraciclib sensitivity, increased mTOR-dependent correlates with sensitivity lines. Reverting growth-promoting mutation PIK3CA wild type CDK7i. Our work establishes enhanced alone CDK7i providing explanation why some cancers are more CDK than normally growing cells.

Язык: Английский

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

Drug Resistance Updates, Год журнала: 2024, Номер 76, С. 101103 - 101103

Опубликована: Июнь 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

Язык: Английский

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Metabolic remodeling in cancer and senescence and its therapeutic implications

Trends in Endocrinology and Metabolism, Год журнала: 2024, Номер 35(8), С. 732 - 744

Опубликована: Март 6, 2024

Язык: Английский

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The search for CDK4/6 inhibitor biomarkers has been hampered by inappropriate proliferation assays

npj Breast Cancer, Год журнала: 2024, Номер 10(1)

Опубликована: Март 4, 2024

CDK4/6 inhibitors are effective at treating advanced HR+ /HER2- breast cancer, however biomarkers that can predict response urgently needed. We demonstrate here previous large-scale screens designed to identify which tumour types or genotypes most sensitive have misrepresented the responsive cell lines because of a reliance on metabolic proliferation assays. CDK4/6-inhibited cells arrest in G1 but continue grow size, thereby producing more mitochondria. show this growth obscures using ATP-based assays not if DNA-based used instead. Furthermore, lymphoma lines, previously identified as sensitive, simply appear respond best they fail overgrow during arrest. Similarly, inhibitor abemaciclib appears inhibit better than palbociclib it also restricts cellular overgrowth through off-target effects. DepMap analysis screening data reliable assay types, demonstrates palbociclib-sensitive Cyclin D1, CDK4 and CDK6 knockout/knockdown, whereas palbociclib-resistant E1, CDK2 SKP2 knockout/knockdown. Potential increased expression CCND1 RB1, reduced CCNE1 CDKN2A. Probing with similar from fails reveal these associations. Together, why inhibitors, any other anti-cancer drugs cycle permit continued growth, must now be re-screened against wide-range an appropriate assay. This would help inform clinical trials much needed response.

Язык: Английский

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Genome dilution by cell growth drives starvation-like proteome remodeling in mammalian and yeast cells

Nature Structural & Molecular Biology, Год журнала: 2024, Номер unknown

Опубликована: Июль 24, 2024

Язык: Английский

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Cell enlargement modulated by GATA4 and YAP instructs the senescence-associated secretory phenotype

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 17, 2025

Dynamic changes in cell size are associated with development and pathological conditions, including aging. Although enlargement is a prominent morphological feature of cellular senescence, its functional implications unknown; moreover, how senescent cells maintain their state less understood. Here we show that an extensive remodeling actin cytoskeleton necessary for establishing senescence-associated pro-inflammatory secretory phenotype (SASP). This attributed to balancing act between the SASP regulator GATA4 mechanosensor YAP on expression Rho family GTPase RHOU. Genetic or pharmacological interventions reduce attenuate minimal effect senescence growth arrest. Mechanistically, couples nuclear localization NF-κB via Linker Nucleoskeleton Cytoskeleton (LINC) complex. RhoU protein accumulates mouse adipose tissue under senescence-inducing conditions. Furthermore, RHOU correlates during human Thus, our study highlights unexpected instructive role modulating reveals mechanical branch regulatory network. Senescent accumulate aging exhibit enlargement, function which has been unclear decades. Here, authors identify antagonistic genetic circuit hypertrophy reveal SASP.

Язык: Английский

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Eukaryotic cell size regulation and its implications for cellular function and dysfunction

Physiological Reviews, Год журнала: 2024, Номер 104(4), С. 1679 - 1717

Опубликована: Июнь 20, 2024

Depending on cell type, environmental inputs, and disease, the cells in human body can have widely different sizes. In recent years, it has become clear that size is a major regulator of function. However, we are only beginning to understand how optimization function determines given cell’s optimal size. Here, review currently known control strategies eukaryotic intricate link intracellular biomolecular scaling, organelle homeostasis, cycle progression. We detail size-dependent regulation early development impact differentiation. Given importance for normal cellular physiology, must account changing conditions. describe sense stimuli, such as nutrient availability, accordingly adapt their by regulating growth Moreover, discuss correlation pathological states with misregulation long time this was considered downstream consequence dysfunction. newer studies reveal reversed causality, misregulated leading pathophysiological phenotypes senescence aging. summary, highlight important roles dysfunction, which could implications both diagnostics treatment clinic.

Язык: Английский

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