INX-315, a Selective CDK2 Inhibitor, Induces Cell Cycle Arrest and Senescence in Solid Tumors

Cancer Discovery, Journal Year: 2023, Volume and Issue: 14(3), P. 446 - 467

Published: Dec. 1, 2023

Cyclin-dependent kinase 2 (CDK2) is thought to play an important role in driving proliferation of certain cancers, including those harboring CCNE1 amplification and breast cancers that have acquired resistance CDK4/6 inhibitors (CDK4/6i). The precise impact pharmacologic inhibition CDK2 not known due the lack selective inhibitors. Here we describe INX-315, a novel potent inhibitor with high selectivity over other CDK family members. Using cell-based assays, patient-derived xenografts (PDX), transgenic mouse models, show INX-315 (i) promotes retinoblastoma protein hypophosphorylation therapy-induced senescence (TIS) CCNE1-amplified tumors, leading durable control tumor growth; (ii) overcomes cancer CDK4/6i, restoring cell cycle while reinstating chromatin architecture CDK4/6i-induced TIS; (iii) delays onset CDK4/6i by deeper suppression E2F targets. Our results support clinical development novel, CDK2. preclinical studies demonstrate activity for both CDK4/6i-resistant cancer. In each case, induces arrest phenotype resembling cellular senescence. data trials. See related commentary Watts Spencer, p. 386. This article featured Selected Articles from Issue, 384.

Language: Английский

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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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Role of LMO7 in cancer (Review)

Oncology Reports, Journal Year: 2024, Volume and Issue: 52(3)

Published: July 11, 2024

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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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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CDK2 and CDK4: Cell Cycle Functions Evolve Distinct, Catalysis-Competent Conformations, Offering Drug Targets

JACS Au, Journal Year: 2024, Volume and Issue: 4(5), P. 1911 - 1927

Published: May 14, 2024

Cyclin-dependent kinases (CDKs), particularly CDK4 and CDK2, are crucial for cell cycle progression from the Gap 1 (G1) to Synthesis (S) phase by phosphorylating targets such as Retinoblastoma Protein (Rb). CDK4, paired with cyclin-D, operates in long G1 phase, while CDK2 cyclin-E, manages brief G1-to-S transition, enabling DNA replication. Aberrant CDK signaling leads uncontrolled proliferation, which is a hallmark of cancer. Exactly how they accomplish their catalytic phosphorylation actions distinct efficiencies poses fundamental, albeit overlooked question. Here we combined available experimental data modeling active complexes establish conformational functional landscapes explain two cyclin/CDK differentially populate catalytically competent states progression. Our premise that could be more important than cyclin-CDK biochemical binding specificity efficiency likely prime determinant We observe dynamic ATP site, regulatory spine, interaction its cyclin partner. The N-terminus cyclin-D acts an allosteric regulator activation loop ATP-binding site CDK4. Integrated suite data, suggest complex less capable remaining conformation, may have lower befitting time scales, point critical residues motifs drive differences. mechanistic landscape apply broadly kinases, propose drug design strategies: (i) Inhibition stabilization targeting regulation (ii) entropy-optimized leverages dynamic, entropic aspects optimize efficacy.

Language: Английский

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Optimizing therapeutic approaches for HR+/HER2- advanced breast cancer: clinical perspectives on biomarkers and treatment strategies post-CDK4/6 inhibitor progression

Cancer Drug Resistance, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

This review offers an expert perspective on biomarkers, CDK4/6 inhibitor efficacy, and therapeutic approaches for managing hormone receptor-positive (HR+), human epidermal growth factor receptor-negative (HER2-) advanced breast cancer (ABC), particularly after progression. Key trials have demonstrated that combining inhibitors with endocrine therapy (ET) significantly improves progression-free survival (PFS), median durations ranging from 14.8 to 26.7 months, overall (OS), reaching up 53.7 months. Actionable such as PIK3CA ESR1 mutations, emerged pivotal tools guide second-line treatment decisions, enabling the use of targeted therapies like alpelisib elacestrant emphasizing important role biomarkers in guiding selection therapy. overview aims provide clinicians a practical up-to-date framework inform decisions improve patient care context this challenging disease. Additionally, we emerging novel strategies address difficult clinical landscape.

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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Transient silencing of hypermutation preserves B cell affinity during clonal bursting

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: March 19, 2025

Abstract In the course of antibody affinity maturation, germinal centre (GC) B cells mutate their immunoglobulin heavy- and light-chain genes in a process known as somatic hypermutation (SHM) 1–4 . Panels mutant with different binding affinities for antigens are then selected Darwinian manner, which leads to progressive increase among population 5 As any process, rare gain-of-fitness mutations must be identified common loss-of-fitness avoided 6 Progressive acquisition therefore poses risk during large proliferative bursts 7 , when GC undergo several cell cycles absence affinity-based selection 8–13 Using combination vivo mouse experiments mathematical modelling, here we show that GCs achieve this balance by strongly suppressing SHM clonal-burst-type expansion, so fraction progeny generated these does not deviate from ancestral genotype. Intravital imaging image-based sorting strain carrying reporter cyclin-dependent kinase 2 (CDK2) activity showed actively undergoing lack transient CDK2 low ‘G0-like’ phase cycle takes place. We propose model inertially cycling mostly delay until G0-like follows final round division dark zone, thus maintaining they clonally expand selection.

Language: Английский

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Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 8, 2024

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and emerging therapeutic target that overexpressed in most castration-resistant prostate cancers implicated as driver disease progression resistance to hormonal therapies. Here we define the lineage-specific action differential activity EZH2 both adenocarcinoma neuroendocrine cancer (NEPC) subtypes advanced better understand role modulating differentiation, lineage plasticity, identify mediators response inhibitor therapy. Mechanistically, modulates bivalent genes results upregulation NEPC-associated transcriptional drivers (e.g., ASCL1) neuronal gene programs NEPC, leads forward differentiation after targeting NEPC. Subtype-specific downstream effects inhibition on cell cycle support potential rationale for co-targeting cyclin/CDK overcome inhibition. has been Here, authors focus two report how it thereby leading being targeted cancer.

Language: Английский

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