Cell cycle proteins as promising targets in cancer therapy

Nature reviews. Cancer, Journal Year: 2017, Volume and Issue: 17(2), P. 93 - 115

Published: Jan. 27, 2017

Language: Английский

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Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways

Cancers, Journal Year: 2017, Volume and Issue: 9(5), P. 52 - 52

Published: May 17, 2017

The epidermal growth factor receptor (EGFR) is a tyrosine kinase that commonly upregulated in cancers such as non-small-cell lung cancer, metastatic colorectal glioblastoma, head and neck pancreatic breast cancer. Various mechanisms mediate the upregulation of EGFR activity, including common mutations truncations to its extracellular domain, EGFRvIII truncations, well L858R T790M mutations, or exon 19 truncation. These aberrations over-activate downstream pro-oncogenic signaling pathways, RAS-RAF-MEK-ERK MAPK AKT-PI3K-mTOR pathways. pathways then activate many biological outputs are beneficial cancer cell proliferation, their chronic initiation progression through cycle. Here, we review molecular regulate signal transduction, structure ligand binding dimerization, lead G1 cycle progression. We focus on induction CYCLIN D expression, CDK4/6 activation, repression cyclin-dependent inhibitor proteins (CDKi) by also discuss successes challenges EGFR-targeted therapies, potential for use combination with inhibitors.

Language: Английский

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Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer

New England Journal of Medicine, Journal Year: 2015, Volume and Issue: 373(3), P. 209 - 219

Published: June 1, 2015

Growth of hormone-receptor-positive breast cancer is dependent on cyclin-dependent kinases 4 and 6 (CDK4 CDK6), which promote progression from the G1 phase to S cell cycle. We assessed efficacy palbociclib (an inhibitor CDK4 CDK6) fulvestrant in advanced cancer.This 3 study involved 521 patients with hormone-receptor-positive, human epidermal growth factor receptor 2-negative that had relapsed or progressed during prior endocrine therapy. randomly assigned a 2:1 ratio receive placebo fulvestrant. Premenopausal perimenopausal women also received goserelin. The primary end point was investigator-assessed progression-free survival. Secondary points included overall survival, objective response, rate clinical benefit, patient-reported outcomes, safety. A preplanned interim analysis performed by an independent data safety monitoring committee after 195 events disease death occurred.The median survival 9.2 months (95% confidence interval [CI], 7.5 not estimable) palbociclib-fulvestrant 3.8 CI, 3.5 5.5) placebo-fulvestrant (hazard for death, 0.42; 95% 0.32 0.56; P<0.001). most common grade adverse group were neutropenia (62.0%, vs. 0.6% group), leukopenia (25.2% 0.6%), anemia (2.6% 1.7%), thrombocytopenia (2.3% 0%), fatigue (2.0% 1.2%). Febrile reported palbociclib-treated placebo-treated patients. discontinuation due 2.6% 1.7% placebo.Among metastatic who therapy, combined resulted longer than alone. (Funded Pfizer; PALOMA3 ClinicalTrials.gov number, NCT01942135.).

Language: Английский

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Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: May 31, 2021

Abstract Due to the advantages in efficacy and safety compared with traditional chemotherapy drugs, targeted therapeutic drugs have become mainstream cancer treatments. Since first tyrosine kinase inhibitor imatinib was approved enter market by US Food Drug Administration (FDA) 2001, an increasing number of small-molecule been developed for treatment malignancies. By December 2020, 89 antitumor FDA National Medical Products (NMPA) China. Despite great progress, anti-cancer still face many challenges, such as a low response rate drug resistance. To better promote development we conducted comprehensive review according target classification. We present all well important candidates clinical trials each target, discuss current provide insights perspectives research drugs.

Language: Английский

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Treating cancer with selective CDK4/6 inhibitors

Nature Reviews Clinical Oncology, Journal Year: 2016, Volume and Issue: 13(7), P. 417 - 430

Published: March 31, 2016

Language: Английский

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Tau-targeting therapies for Alzheimer disease

Nature Reviews Neurology, Journal Year: 2018, Volume and Issue: 14(7), P. 399 - 415

Published: June 12, 2018

Language: Английский

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Targeting CDK4 and CDK6: From Discovery to Therapy

Cancer Discovery, Journal Year: 2015, Volume and Issue: 6(4), P. 353 - 367

Published: Dec. 12, 2015

Biochemical and genetic characterization of D-type cyclins, their cyclin D-dependent kinases (CDK4 CDK6), the polypeptide CDK4/6 inhibitor p16(INK4)over two decades ago revealed how mammalian cells regulate entry into DNA synthetic (S) phase cell-division cycle in a retinoblastoma protein-dependent manner. These investigations provided proof-of-principle that inhibitors, particularly when combined with coinhibition allied mitogen-dependent signal transduction pathways, might prove valuable cancer therapy. FDA approval palbociclib used aromatase letrozole for breast treatment highlights long-sought success. The newest findings herald clinical trials targeting other cancers.Rapidly emerging data selective inhibitors have validated these cell-cycle as anticancer drug targets, corroborating longstanding preclinical predictions. This review addresses discovery CDKs regulators, well translation biology to positive outcomes development rational combinatorial therapies.

Language: Английский

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Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor–Positive Breast Cancer

Cancer Research, Journal Year: 2016, Volume and Issue: 76(8), P. 2301 - 2313

Published: March 29, 2016

Small-molecule inhibitors of the CDK4/6 cell-cycle kinases have shown clinical efficacy in estrogen receptor (ER)-positive metastatic breast cancer, although their cytostatic effects are limited by primary and acquired resistance. Here we report that ER-positive cancer cells can adapt quickly to inhibition evade cytostasis, part, via noncanonical cyclin D1-CDK2-mediated S-phase entry. This adaptation was prevented cotreatment with hormone therapies or PI3K inhibitors, which reduced levels D1 (CCND1) other G1-S cyclins, abolished pRb phosphorylation, inhibited activation transcriptional programs. Combined targeting both triggered cell apoptosis vitro patient-derived tumor xenograft (PDX) models, resulting regression improved disease control. Furthermore, a triple combination endocrine therapy, CDK4/6, more effective than paired combinations, provoking rapid regressions PDX model. Mechanistic investigations showed resistance resulted from bypass D1-CDK4/6 dependency through selection CCNE1 amplification RB1 loss. Notably, could prevent they failed resensitize once had been acquired. However, found acquiring due be resensitized CDK2. Overall, our results illustrate convergent mechanisms early enable alternate means entry, highlighting strategies acquisition therapeutic these agents. Cancer Res; 76(8); 2301-13. ©2016 AACR.

Language: Английский

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CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation

Cancer Discovery, Journal Year: 2017, Volume and Issue: 8(2), P. 216 - 233

Published: Nov. 4, 2017

Immune checkpoint blockade, exemplified by antibodies targeting the PD-1 receptor, can induce durable tumor regressions in some patients. To enhance efficacy of existing immunotherapies, we screened for small molecules capable increasing activity T cells suppressed PD-1. Here, show that short-term exposure to small-molecule inhibitors cyclin-dependent kinases 4 and 6 (CDK4/6) significantly enhances T-cell activation, contributing antitumor effects vivo, due part derepression NFAT family proteins their target genes, critical regulators function. Although CDK4/6 decrease proliferation, they increase infiltration activation effector cells. Moreover, inhibition augments response blockade a novel ex vivo organotypic spheroid culture system multiple murine syngeneic models, thereby providing rationale combining immunotherapies.Significance: Our results define previously unrecognized immunomodulatory functions suggest with immune may treatment Furthermore, our study highlights importance identifying complementary strategies improve immunotherapy patients cancer. Cancer Discov; 8(2); 216-33. ©2017 AACR.See related commentary Balko Sosman, p. 143See article Jenkins et al., 196This is highlighted In This Issue feature, 127.

Language: Английский

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A perspective on multi‐target drug discovery and design for complex diseases

Clinical and Translational Medicine, Journal Year: 2018, Volume and Issue: 7(1)

Published: Jan. 11, 2018

Diseases of infection, neurodegeneration (such as Alzheimer's and Parkinson's diseases), malignancy (cancers) have complex varied causative factors. Modern drug discovery has the power to identify potential modulators for multiple targets from millions compounds. Computational approaches allow determination association each compound with its target before chemical synthesis biological testing is done. These depend on prior identification clinically biologically validated targets. This Perspective will focus molecular computational that underpin design by medicinal chemists promote understanding collaboration clinical scientists.

Language: Английский

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