MYH knockdown in pancreatic cancer cells creates an exploitable DNA repair vulnerability

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia Pub Date : 2025-02-11 DOI:10.1016/j.neo.2025.101138

James Ephraums , Janet Youkhana , Aparna S. Raina , Grace Schulstad , Kento Croft , Amanda Mawson , John Kokkinos , Estrella Gonzales-Aloy , Rosa Mistica C. Ignacio , Joshua A. McCarroll , Cyrille Boyer , David Goldstein , Marina Pajic , Koroush S. Haghighi , Amber Johns , Anthony J. Gill , Mert Erkan , Australian Pancreatic Cancer Genome Initiative (APGI) , Phoebe A. Phillips , George Sharbeen

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引用次数: 0

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate of just 13 %. Conventional therapies fail due to acquired chemoresistance. We previously identified MutY-Homolog (MYH), a protein that repairs oxidative DNA damage, as a therapeutic target that induces apoptosis in PDAC cells. However, we did not understand the mechanism driving these anti-PDAC effects, nor did we have a means to therapeutically inhibit MYH. In this study, we demonstrated that MYH inhibition induces DNA damage and checkpoint activation in PDAC cells. Using a clinically-relevant PDAC mouse model, we showed that therapeutic MYH-siRNA delivery using Star 3 nanoparticles increased intratumoural PDAC cell death, but did not inhibit tumour growth. Finally, we showed that MYH knockdown in PDAC cells sensitised them to the anti-proliferative and anti-clonogenic effects of oxaliplatin and olaparib. Our findings identify a potential novel therapeutic approach for PDAC that induces a therapeutically exploitable DNA repair vulnerability.

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胰腺癌细胞中MYH的敲除产生了可利用的DNA修复脆弱性

胰腺导管腺癌（PDAC）的5年生存率只有13%。常规治疗因获得性化疗耐药而失败。我们之前鉴定了MYH（一种修复DNA氧化损伤的蛋白）作为诱导PDAC细胞凋亡的治疗靶点。然而，我们不了解驱动这些抗pdac作用的机制，也没有治疗性抑制MYH的方法。在这项研究中，我们证明了MYH抑制诱导PDAC细胞的DNA损伤和检查点激活。使用临床相关的PDAC小鼠模型，我们发现使用Star 3纳米颗粒递送治疗性MYH-siRNA增加了肿瘤内PDAC细胞死亡，但没有抑制肿瘤生长。最后，我们发现PDAC细胞中的MYH敲低使它们对奥沙利铂和奥拉帕尼的抗增殖和抗克隆作用敏感。我们的研究结果确定了一种潜在的新的PDAC治疗方法，即诱导可用于治疗的DNA修复脆弱性。

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来源期刊

Neoplasia 医学-肿瘤学

CiteScore

9.20

自引率

2.10%

发文量

审稿时长

26 days

期刊介绍： Neoplasia publishes the results of novel investigations in all areas of oncology research. The title Neoplasia was chosen to convey the journal’s breadth, which encompasses the traditional disciplines of cancer research as well as emerging fields and interdisciplinary investigations. Neoplasia is interested in studies describing new molecular and genetic findings relating to the neoplastic phenotype and in laboratory and clinical studies demonstrating creative applications of advances in the basic sciences to risk assessment, prognostic indications, detection, diagnosis, and treatment. In addition to regular Research Reports, Neoplasia also publishes Reviews and Meeting Reports. Neoplasia is committed to ensuring a thorough, fair, and rapid review and publication schedule to further its mission of serving both the scientific and clinical communities by disseminating important data and ideas in cancer research.