PKMYT1 Is a Marker of Treatment Response and a Therapeutic Target for CDK4/6 Inhibitor-Resistance in ER+ Breast Cancer.

IF 5.3 2区医学 Q1 ONCOLOGY

Molecular Cancer Therapeutics Pub Date : 2024-10-01 DOI:10.1158/1535-7163.MCT-23-0564

Anran Chen, Beom-Jun Kim, Aparna Mitra, Craig T Vollert, Jonathan T Lei, Diana Fandino, Meenakshi Anurag, Matthew V Holt, Xuxu Gou, Jacob B Pilcher, Matthew P Goetz, Donald W Northfelt, Susan G Hilsenbeck, C Gary Marshall, Marc L Hyer, Robert Papp, Shou-Yun Yin, Carmine De Angelis, Rachel Schiff, Suzanne A W Fuqua, Cynthia X Ma, Charles E Foulds, Matthew J Ellis

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引用次数: 0

Abstract

Endocrine therapies (ET) with cyclin-dependent kinase 4/6 (CDK4/6) inhibition are the standard treatment for estrogen receptor-α-positive (ER+) breast cancer, however drug resistance is common. In this study, proteogenomic analyses of patient-derived xenografts (PDXs) from patients with 22 ER+ breast cancer demonstrated that protein kinase, membrane-associated tyrosine/threonine one (PKMYT1), a WEE1 homolog, is estradiol (E2) regulated in E2-dependent PDXs and constitutively expressed when growth is E2-independent. In clinical samples, high PKMYT1 mRNA levels associated with resistance to both ET and CDK4/6 inhibition. The PKMYT1 inhibitor lunresertib (RP-6306) with gemcitabine selectively and synergistically reduced the viability of ET and palbociclib-resistant ER+ breast cancer cells without functional p53. In vitro the combination increased DNA damage and apoptosis. In palbociclib-resistant, TP53 mutant PDX-derived organoids and PDXs, RP-6306 with low-dose gemcitabine induced greater tumor volume reduction compared to treatment with either single agent. Our study demonstrates the clinical potential of RP-6306 in combination with gemcitabine for ET and CDK4/6 inhibitor resistant TP53 mutant ER+ breast cancer.

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PKMYT1是ER+乳腺癌治疗反应的标记物和CDK4/6抑制剂耐药性的治疗靶点

抑制CDK4/6的内分泌疗法（ET）是治疗雌激素受体α阳性（ER+）乳腺癌的标准疗法，但耐药性很常见。在这项研究中，对22个ER+乳腺癌患者衍生异种移植物（PDXs）进行的蛋白质基因组学分析表明，WEE1同源物PKMYT1在依赖雌激素（E2）的PDXs中受雌二醇（E2）调控，而在不依赖E2生长的PDXs中则呈组成型表达。在临床样本中，高水平的 PKMYT1 mRNA 与对 ET 和 CDK4/6 抑制的耐受性有关。PKMYT1 抑制剂 lunresertib（RP-6306）与吉西他滨可选择性地协同降低对 ET 和帕博西尼耐药的无功能 p53 的 ER+ 乳腺癌细胞的活力。在体外，该组合可增加 DNA 损伤和细胞凋亡。在palbociclib耐药、TP53突变的PDX器官组织和异种移植物中，RP-6306与低剂量吉西他滨联合用药与单药治疗相比，能诱导更大的肿瘤体积缩小。我们的研究证明了RP-6306与吉西他滨联合治疗ET和CDK4/6抑制剂耐药的TP53突变ER+乳腺癌的临床潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Cancer Therapeutics 医学-肿瘤学

CiteScore

11.20

自引率

1.80%

发文量

331

审稿时长

3 months

期刊介绍： Molecular Cancer Therapeutics will focus on basic research that has implications for cancer therapeutics in the following areas: Experimental Cancer Therapeutics, Identification of Molecular Targets, Targets for Chemoprevention, New Models, Cancer Chemistry and Drug Discovery, Molecular and Cellular Pharmacology, Molecular Classification of Tumors, and Bioinformatics and Computational Molecular Biology. The journal provides a publication forum for these emerging disciplines that is focused specifically on cancer research. Papers are stringently reviewed and only those that report results of novel, timely, and significant research and meet high standards of scientific merit will be accepted for publication.