CRISPR Screens Identify PIK3C2A as a Novel Mediator of EGFR Inhibitor Resistance in Head and Neck Squamous Cell Carcinoma.

IF 2.2 3区医学 Q1 OTORHINOLARYNGOLOGY

Head and Neck-Journal for the Sciences and Specialties of the Head and Neck Pub Date : 2025-09-23 DOI:10.1002/hed.70048

Jiayu Wang, Megan L Ludwig, Aditi Kulkarni, Andrew C Birkeland, Nicole L Michmerhuizen, Elizabeth Gensterblum-Miller, Jingyi Zhai, Hui Jiang, Paul Swiecicki, Marisa Buchakjian, Molly Heft Neal, Steven B Chinn, Matthew E Spector, J Chad Brenner

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引用次数: 0

Abstract

Background: Head and neck squamous cell carcinoma (HNSCC) is a malignancy with poor prognosis and survival. While epidermal growth factor receptor (EGFR) is a known driver of HNSCC, EGFR inhibitors show limited efficacy as monotherapies, suggesting that effective combination therapies are needed.

Methods: We performed GeCKO and Kinase CRISPR library screens to identify candidate knockouts that increase EGFR inhibitor sensitivity in resistant HNSCC cells. We validated a candidate using the CellTiter-Glo viability assay following RNA interference and investigated the mechanisms using apoptosis and cell cycle flow cytometry analysis.

Results: Kinase CRISPR library screens identified that PIK3C2A gene downregulation enhanced EGFR inhibitor sensitivity in resistant HNSCC cells. Viability assays further validated that PIK3C2A knockdown overcame EGFR inhibitor resistance in HNSCC cells.

Conclusions: Our data suggests that PIK3C2A is a novel mediator of EGFR inhibitor resistance in HNSCC. Future studies are required to determine the mechanisms by which PIK3C2A drives EGFR inhibitor resistance.

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CRISPR筛选发现PIK3C2A是头颈部鳞状细胞癌中EGFR抑制剂耐药的新介质

背景：头颈部鳞状细胞癌（HNSCC）是一种预后差、生存期差的恶性肿瘤。虽然表皮生长因子受体（EGFR）是已知的HNSCC的驱动因素，但EGFR抑制剂作为单一治疗的疗效有限，这表明需要有效的联合治疗。方法：我们进行了GeCKO和激酶CRISPR文库筛选，以确定在耐药的HNSCC细胞中增加EGFR抑制剂敏感性的候选敲除。我们使用RNA干扰后的CellTiter-Glo活力测定验证了候选细胞，并使用细胞凋亡和细胞周期流式细胞术分析研究了其机制。结果：激酶CRISPR文库筛选发现，PIK3C2A基因下调可增强耐药HNSCC细胞中EGFR抑制剂的敏感性。活性分析进一步证实，PIK3C2A敲低克服了HNSCC细胞中EGFR抑制剂的耐药性。结论：我们的数据表明PIK3C2A是HNSCC中EGFR抑制剂耐药的一种新的介质。未来的研究需要确定PIK3C2A驱动EGFR抑制剂耐药的机制。

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

Head and Neck-Journal for the Sciences and Specialties of the Head and Neck 医学-耳鼻喉科学

CiteScore

7.00

自引率

6.90%

发文量

278

审稿时长

1.6 months

期刊介绍： Head & Neck is an international multidisciplinary publication of original contributions concerning the diagnosis and management of diseases of the head and neck. This area involves the overlapping interests and expertise of several surgical and medical specialties, including general surgery, neurosurgery, otolaryngology, plastic surgery, oral surgery, dermatology, ophthalmology, pathology, radiotherapy, medical oncology, and the corresponding basic sciences.