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

---

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

---

Everolimus plus endocrine therapy beyond CDK4/6 inhibitors progression for HR+ /HER2− advanced breast cancer: a real-world evidence cohort

Breast Cancer Research and Treatment, Journal Year: 2024, Volume and Issue: 206(3), P. 551 - 559

Published: May 4, 2024

Language: Английский

---

Health care resource utilization and costs of Medicare-enrolled patients with HR+/HER2− metastatic breast cancer treated with a CDK4/6i in the first-line setting

Journal of Managed Care & Specialty Pharmacy, Journal Year: 2025, Volume and Issue: 31(1), P. 6 - 14

Published: Jan. 1, 2025

The introduction of cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6is) has transformed the treatment landscape for patients with hormone receptor positive (HR+) human epidermal growth factor 2 negative (HER2-) metastatic breast cancer (MBC). To our knowledge, no studies have quantified health care resource utilization (HRU) or economic burden following CDK4/6i initiation in Medicare population.

Language: Английский

---

Systematic Review and Network Meta-Analysis on Treating Hormone Receptor-Positive Metastatic Breast Cancer After CDK4/6 Inhibitors

Current Oncology, Journal Year: 2025, Volume and Issue: 32(1), P. 53 - 53

Published: Jan. 20, 2025

Introduction: The optimal treatment of estrogen receptor-positive (ER +) metastatic breast cancer (MBC) after progression on cyclin-dependent 4/6 kinase inhibitors (CDK4/6i) is unknown. Methods: We conducted a systematic review and network meta-analysis (NMA) phase-II/-III randomized trials ER + MBC post CDK4/6i ET progression. calculated the hazard ratio (HR) for progression-free survival (PFS) overall (OS) using generic inverse variance odds ratios (ORs) Mantel–Haenszel method adverse events (AEs) with Review-Manager version-5.4. NMA was executed WINBUGS (Microsoft Excel). Three molecular subgroups were analyzed: HER2-low, PI3K/AKT/mTOR, ESR1 mutation subgroup selective receptor degrader (SERD). Results: A total 14 studies included. In HER2-low group, Sacituzumab govitecan trastuzumab deruxtecan had similar efficacy (HR, 95% CI): PFS (0.98; 0.63–1.43) OS (1.08; 0.76–1.55). PI3K/AKT/mTOR-altered cases, capivasertib superior to alpelisib (0.77; 0.53–1.12), (0.80; 0.48–1.35). SERDs worse versus ongoing CDK 4/6i (ribociclib). Conclusion: No therapy emerged as unequivocal choice in post-CDK domain unselected subgroups. population, different toxicity spectrum seen. AKT-altered tumors, less toxic than alpelisib. PROSPERO ID: CRD4202236412.

Language: Английский

---

Survival Following CDK4/6 Inhibitor Therapy for Hormone Receptor–Positive, ERBB2–Negative Metastatic Breast Cancer

JAMA Network Open, Journal Year: 2025, Volume and Issue: 8(2), P. e2461067 - e2461067

Published: Feb. 21, 2025

Endocrine therapy (ET) combined with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) agents is the standard first-line treatment for patients hormone receptor-positive, ERBB2 (formerly HER2 or HER2/neu)-negative metastatic breast cancer. However, optimal after tumor progression to ET plus CDK4/6i remains unclear. To evaluate progression-free survival (PFS) and overall (OS) in clinical practice setting ERBB2-negative cancer following CDK4/6i. The multicenter retrospective cohort study included 506 diagnosed between April 22, 2015, January 31, 2023, who received ET-based chemotherapy (CT)-based during Outcomes were analyzed based on type, clinicopathologic features, duration of prior therapy. primary end point was PFS setting, defined as time initiation first systemic detection disease patient death from any cause. secondary OS interval In women (median age at diagnosis, 52.4 [IQR, 44.6-62.8] years) progressing CDK4/6i, independent factors associated poorer outcomes visceral metastases (hazard ratio [HR], 1.45; 95% CI, 1.17-1.80; P = .008) de novo (HR, 1.25; 1.01-1.54; .04). A longer (OS HR, 0.55; 0.41-0.73; < .001) an older (PFS 0.99; CI 0.98-1.00; .03) better outcomes. Compared oral CT, both intravenous CT- treatments shorter (intravenous CT: hazard 1.11-1.89; .006; everolimus exemestane: 1.38; 1.06-1.78; .02; only: 1.05-1.89; .02). exceeding 12 months .001). Among metastases, CT compared 1.52; 1.03-2.24; this study, control achieved CDK4/6i-based presence emerged key that may affect decision. Oral offer potential benefits specific subgroups.

Language: Английский

---

Targeting cyclin-dependent kinase 2 (CDK2) interactions with cyclins and Speedy 1 (Spy1) for cancer and male contraception

Future Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 21

Published: March 4, 2025

The review discusses progress in discovering cyclin-dependent kinase 2 (CDK2) inhibitors for cancer treatment and their potential male contraception. It summarizes first-, second-, third-generation CDK selective CDK2 currently clinical trials cancer. Novel strategies to discover allosteric inhibitors, covalent degraders are also discussed.

Language: Английский

---

Oral selective estrogen receptor degraders (SERDs) in Hormone receptor-Positive HER2-Negative Metastatic breast cancer After Progression with CDK4/6 inhibitors

Expert Review of Anticancer Therapy, Journal Year: 2025, Volume and Issue: unknown

Published: March 13, 2025

Hormone receptor-positive (HR+), HER2-negative metastatic breast cancer (mBC) remains a prevalent and challenging disease. Endocrine therapy (ET) combined with CDK4/6 inhibitors is the first-line standard of care, yet resistance mechanisms, including ESR1 mutations, drive disease progression. Novel oral selective estrogen receptor degraders (SERDs) have emerged as promising therapeutic agents after progression secondary to mutations. However, available studies on SERDs differ in design, study population, outcomes, necessitating critical review data. This explores clinical efficacy, safety profiles HR-positive, mBC, particularly following inhibitors. Recent key trials, EMERALD, SERENA-2, EMBER-3 AMEERA-3, are analyzed, highlighting their efficacy overcoming resistance, especially ESR1-mutant populations. Oral offer enhanced bioavailability convenience compared fulvestrant, representing advancement endocrine therapy. Their integration into treatment strategies, combination regimens ctDNA-driven approaches, may improve patient outcomes address mechanisms. other than refinement for selection limited. Further trials needed optimize SERD use define most effective strategies SERDs.

Language: Английский

---

Effect of Tasurgratinib as an Orally Available FGFR1–3 Inhibitor on Resistance to a CDK4/6 Inhibitor and Endocrine Therapy in ER+/HER2− Breast Cancer Preclinical Models

Cancers, Journal Year: 2025, Volume and Issue: 17(7), P. 1084 - 1084

Published: March 24, 2025

Fibroblast growth factor (FGF) signaling plays a crucial role in several cellular functions cancer cells. Tasurgratinib, formerly known as E7090, is an orally available FGF receptor (FGFR)1-3 selective inhibitor. Here, we present the effects of tasurgratinib on resistance to CDK4/6 inhibitors and endocrine therapy (ET) preclinical model. Estrogen (ER)+ breast (BC) patient-derived xenograft (PDX) models harboring ESR1 wild-type or mutation were used animal models. An vitro cell proliferation assay ER+ BC lines treated with fulvestrant palbociclib + was conducted presence FGF2 FGF10, without tasurgratinib. Among five PDX models, OD-BRE-0438 OD-BRE-0704 showed higher sensitivities prior than it. In these treatment upregulated expression ligand mRNAs. vitro, FGF10 decreased sensitivity both fulvestrant, which restored by co-treatment Consistently, elacestrant antitumor activity mutation, respectively. ET BC. Tasurgratinib has potential exhibit significant combination against via inhibition. These findings indicate therapeutic treating

Language: Английский

---

Elacestrant for ER-Positive HER2-Negative Advanced Breast Cancer

Annals of Pharmacotherapy, Journal Year: 2023, Volume and Issue: 58(8), P. 849 - 856

Published: Oct. 27, 2023

Objective: This article aims to discuss elacestrant, an oral selective estrogen receptor downregulator approved by the Food and Drug Administration (FDA) in January 2023 for treatment of hormone positive (HR+) human epidermal growth factor 2 negative (HER2−) advanced breast cancer. Data sources: PubMed, Embase, Medline, Clinicaltrials.gov, National Comprehensive Cancer Network (NCCN) were searched from inception August 31, 2023. Study selection data extraction: Clinical trials published English included relevant information regarding methodology results extracted. synthesis: Phase 1 3 showed elacestrant was safe improved progression-free survival patients with endocrine (ESR1) mutations who failed cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) plus prior therapy compared standard care (SOC) (fulvestrant, anastrozole, letrozole, or exemestane monotherapy). Relevance patient clinical practice comparison existing drugs: Elacestrant maintains a comparable adverse event profile other therapies offers alternative typical sequential which can delay use be used after traditional chemotherapy. is currently being studied CDK naïve as component combination first-line could lead future indications. Conclusions: gained FDA approval considered HR+ HER2− cancer ESR1 have progressed despite either 4/6i aromatase inhibitors (AI) fulvestrant

Language: Английский

---