The Renaissance of CDK Inhibitors in Breast Cancer Therapy: An Update on Clinical Trials and Therapy Resistance.
The Renaissance of CDK Inhibitors in Breast Cancer Therapy: An Update on Clinical Trials and Therapy Resistance.
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DOI：
10.3390/cancers14215388
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发表时间：
2022-11-01
期刊：
影响因子：
5.2
通讯作者：
Pestell, Richard
中科院分区：
文献类型：
--
作者：
Abdelmalak, Mary;Singh, Rajanbir;Anwer, Mohammed;Ivanchenko, Pavel;Randhawa, Amritdeep;Ahmed, Myra;Ashton, Anthony W.;Du, Yanming;Jiao, Xuanmao;Pestell, Richard
针对异常细胞周期活性的细胞周期蛋白依赖性激酶抑制剂（palbociclib（Ibrance）、ribociclib（Kisqali）和abemaciclib（Verzenio））已在临床试验中得到广泛评价。在雌激素受体阳性和人表皮生长因子受体2阴性的晚期乳腺癌（包括管腔型B乳腺癌）中，每种药物的无进展生存期和总生存期均显著延迟。由染色体不稳定性驱动的耐药性导致基因组重排、细胞周期组分的激活（Rb−肿瘤中的细胞周期蛋白E/cdk 2、生长因子激活途径中的细胞周期蛋白D1）和免疫应答。耐药肿瘤的分子分析可能为新疗法（brivanib，CYC 065，WEE 1激酶和其他抑制剂）提供合理的基础。管腔型B乳腺癌富含细胞周期蛋白D1过表达和染色体不稳定性基因标记。对于管腔型B乳腺癌中染色体不稳定性的分子机制仍知之甚少。共同靶向染色体不稳定性可能会减少普遍的逃逸机制，降低细胞周期蛋白依赖性激酶抑制剂的有效性。细胞周期蛋白依赖性激酶（CDK）控制癌细胞增殖所必需的细胞周期检查点转换。最近的发展已经说明了乳腺癌的单一CDK抑制剂（CDKI）治疗和联合治疗之间细微的重要差异。目前FDA批准用于乳腺癌治疗的CDKI是选择性抑制CDK 4和CDK 6的口服药物，包括palbociclib（Ibrance），ribociclib（Kisqali）和abemaciclib（Verzenio）。CDKI疗法在激素受体阳性（HR+）和人表皮生长因子受体2阴性（HER 2 −）晚期乳腺癌（ABC）恶性肿瘤中有效，但由于雌激素和孕激素受体过表达而仍然敏感。在内分泌治疗中添加CDK 4/6 I可提高疗效并延缓疾病进展。鉴于CDKI的副作用，确定潜在的新治疗方法以增强CDKI的有效性至关重要。最近的Palbociclib长期研究（包括PALLAS和PENSTRUPE B）未能达到影响无进展生存期的主要终点，这表明需要对细胞周期蛋白/CDK功能进行更深入的机制理解。CDKI对抗肿瘤免疫应答的影响代表了一个很有希望的领域。出现的CDKI治疗耐药性为目前在临床试验中的特定类型的新疗法提供了机会。
Cyclin-dependent kinase inhibitors (palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio)), targeting aberrant cell-cycle activity have been evaluated extensively in clinical trials. Significant delays in progression free survival and overall survival are now documented with each agent in estrogen receptor positive and human epidermal growth factor receptor two negative advanced breast cancer including luminal B breast cancer. Therapy resistance, driven by chromosomal instability, results in genomic rearrangements, activation of cell-cycle components (cyclin E/cdk2 in Rb− tumors, cyclin D1 in growth factor activated pathways), and the immune response. Molecular analysis of therapy resistant tumors may provide the rational basis for new therapies (brivanib, CYC065, WEE1 kinase and other inhibitors). Luminal B breast cancer is enriched for cyclin D1 overexpression and the chromosomal instability gene signature. The molecular mechanisms governing chromosomal instability in luminal B breast cancer remain poorly understood. Co-targeting of chromosomal instability may potentially reduce the prevalent escape mechanisms that reduce the effectiveness of cyclin-dependent kinase inhibitors. Cyclin-dependent kinases (CDKs) govern cell-cycle checkpoint transitions necessary for cancer cell proliferation. Recent developments have illustrated nuanced important differences between mono CDK inhibitor (CDKI) treatment and the combination therapies of breast cancers. The CDKIs that are currently FDA-approved for breast cancer therapy are oral agents that selectively inhibit CDK4 and CDK6, include palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio). CDKI therapy is effective in hormone receptor positive (HR+), and human epidermal growth factor receptor two negative (HER2−) advanced breast cancers (ABC) malignancies, but remains susceptible due to estrogen and progesterone receptor overexpression. Adding a CDK4/6I to endocrine therapy increases efficacy and delays disease progression. Given the side effects of CDKI, identifying potential new treatments to enhance CDKI effectiveness is essential. Recent long-term studies with Palbociclib, including the PALLAS and PENELOPE B, which failed to meet their primary endpoints of influencing progression-free survival, suggest a deeper mechanistic understanding of cyclin/CDK functions is required. The impact of CDKI on the anti-tumor immune response represents an area of great promise. CDKI therapy resistance that arises provides the opportunity for specific types of new therapies currently in clinical trials.
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DOI：
10.1186/s13058-021-01409-8
发表时间：
2021-03-24
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
DeMichele A;Cristofanilli M;Brufsky A;Liu X;Mardekian J;McRoy L;Layman RM;Emir B;Torres MA;Rugo HS;Finn RS
通讯作者：
Finn RS
DOI：
10.1158/1078-0432.ccr-16-2174
发表时间：
2017-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Afghahi A;Timms KM;Vinayak S;Jensen KC;Kurian AW;Carlson RW;Chang PJ;Schackmann E;Hartman AR;Ford JM;Telli ML
通讯作者：
Telli ML
影响因子：
--
作者：
Demuth C;Andersen MN;Jakobsen KR;Madsen AT;Sørensen BS
通讯作者：
Sørensen BS
DOI：
10.1016/j.breast.2020.09.008
发表时间：
2020-12
期刊：
Breast (Edinburgh, Scotland)
影响因子：
--
作者：
Fasching PA;Beck JT;Chan A;De Laurentiis M;Esteva FJ;Jerusalem G;Neven P;Pivot X;Bianchi GV;Martin M;Chandiwana D;Lanoue B;Ridolfi A;Wang Y;Rodriguez Lorenc K;Nusch A
通讯作者：
Nusch A
DOI：
10.1073/pnas.1611839113
发表时间：
2016-09-06
影响因子：
11.1
作者：
Duffy, Supipi;Fam, Hok Khim;Hieter, Philip
通讯作者：
Hieter, Philip