JNK通路抑制介导ER+乳腺癌对联合内分泌治疗和CDK4/6抑制的不敏感。

IF 12.8 1区 医学 Q1 ONCOLOGY
Sarah Alexandrou, Christine S Lee, Kristine J Fernandez, Celine E Wiharja, Leila Eshraghi, John Reeves, Daniel A Reed, Neil Portman, Zoe Phan, Heloisa H Milioli, Iva Nikolic, Antonia L Cadell, David R Croucher, Kaylene J Simpson, Elgene Lim, Theresa E Hickey, Ewan K A Millar, Carla L Alves, Henrik J Ditzel, C Elizabeth Caldon
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引用次数: 0

摘要

CDK4/6抑制剂联合内分泌治疗现在被用作雌激素受体阳性(ER+)乳腺癌患者的一线治疗。虽然这种组合提高了总生存率,但疾病进展的机制仍然知之甚少。在这里,我们使用内分泌敏感的ER+乳腺癌细胞进行了无偏倚的全基因组CRISPR/Cas9敲除筛选,以确定对联合内分泌治疗(他莫昔芬)和CDK4/6抑制剂(帕博西尼)治疗耐药的新驱动因素。我们的筛选发现JNK信号的失活,包括激酶MAP2K7的缺失,是药物不敏感的关键驱动因素。我们开发了多个CRISPR/Cas9敲除ER+乳腺癌细胞系(MCF-7和T-47D)来研究MAP2K7和下游MAPK8和MAPK9缺失的影响。MAP2K7敲除增加了体内转移负荷,导致jnk介导的应激反应受损,并在内分泌治疗和CDK4/6抑制剂治疗后促进细胞存活和减少衰老进入。从机制上讲,这是通过AP-1转录因子c-JUN的缺失发生的,导致对内分泌治疗加CDK4/6抑制的联合反应减弱。此外,对临床数据集的分析发现,JNK通路失活与转移性负担增加有关,在早期和转移性ER+乳腺癌队列中,pJNKT183/Y185活性低与对全身内分泌和CDK4/6抑制剂治疗的较差反应相关。总的来说,我们证明了JNK信号的抑制能够在联合内分泌治疗和CDK4/6抑制期间持续生长。我们的数据为在接受联合内分泌治疗和CDK4/6抑制之前根据JNK通路活性对患者进行分层提供了临床前的理论依据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
JNK pathway suppression mediates insensitivity to combination endocrine therapy and CDK4/6 inhibition in ER+ breast cancer.

CDK4/6 inhibitors in combination with endocrine therapy are now used as front-line treatment for patients with estrogen-receptor positive (ER+) breast cancer. While this combination improves overall survival, the mechanisms of disease progression remain poorly understood. Here, we performed unbiased genome-wide CRISPR/Cas9 knockout screens using endocrine sensitive ER+ breast cancer cells to identify novel drivers of resistance to combination endocrine therapy (tamoxifen) and CDK4/6 inhibitor (palbociclib) treatment. Our screens identified the inactivation of JNK signalling, including loss of the kinase MAP2K7, as a key driver of drug insensitivity. We developed multiple CRISPR/Cas9 knockout ER+ breast cancer cell lines (MCF-7 and T-47D) to investigate the effects of MAP2K7 and downstream MAPK8 and MAPK9 loss. MAP2K7 knockout increased metastatic burden in vivo and led to impaired JNK-mediated stress responses, as well as promoting cell survival and reducing senescence entry following endocrine therapy and CDK4/6 inhibitor treatment. Mechanistically, this occurred via loss of the AP-1 transcription factor c-JUN, leading to an attenuated response to combination endocrine therapy plus CDK4/6 inhibition. Furthermore, analysis of clinical datasets found that inactivation of the JNK pathway was associated with increased metastatic burden, and low pJNKT183/Y185 activity correlated with a poorer response to systemic endocrine and CDK4/6 inhibitor therapies in both early-stage and metastatic ER+ breast cancer cohorts. Overall, we demonstrate that suppression of JNK signalling enables persistent growth during combined endocrine therapy and CDK4/6 inhibition. Our data provides the pre-clinical rationale to stratify patients based on JNK pathway activity prior to receiving combination endocrine therapy and CDK4/6 inhibition.

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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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