尽管人乳头瘤病毒阳性 (HPV) 口咽鳞状细胞癌 (OPSCC) 患者通常具有良好的生存率，但 15-20% 的患者在接受化疗和放疗后会复发。因此，需要治疗失败的生物标志物来指导治疗强度。对主要接受化疗（顺铂）和放疗的 HPV OPSCC 患者进行全基因组测序。然后，我们在体外使用 HPV 细胞系（93VU147T、UMSCC47、UWO37 和 UWO23）和体内探索 LRP1B 的缺失是否足以驱动侵袭性表型，并促进对顺铂和放射治疗的耐药性。通过对三个细胞的综合基因组分析在 HPV OPSCC 肿瘤数据集中，我们发现化疗放疗后复发的样本中富含 LRP1B 缺失。在四种 HPV 细胞系（UWO23、UWO37、UMSCC47 和 93VU147T）中使用 siRNA 进行敲除导致所有病例的增殖增加。在同一细胞系组中，CRISPR/Cas9 删除 LRP1B 显示出与各自的非靶向对照细胞相比，LRP1B 删除细胞的增殖、克隆生长和迁移以及对顺铂和辐射的抵抗力增加。细胞系衍生的异种移植研究表明，与体内对照相比，LRP1B 敲除肿瘤对顺铂和放射治疗更具抵抗力。总之，我们的工作表明 LRP1B 缺失可作为识别治疗耐药 HPV OPSCC 病例的潜在生物标志物。版权所有 © 2023。已发表由爱思唯尔有限公司

Although human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) patients typically experience excellent survival, 15-20 % of patients recur after treatment with chemotherapy and radiation. Therefore, there is a need for biomarkers of treatment failure to guide treatment intensity.Whole genome sequencing was carried out on HPV+OPSCC patients who were primarily treated with concurrent chemotherapy (cisplatin) and radiation. We then explored whether the loss of LRP1Bwas sufficient to drive an aggressive phenotype, and promote a resistance to cisplatin and radiation therapy both in vitro using HPV+ cell lines (93VU147T, UMSCC47, UWO37 and UWO23) and in vivo.Through integrative genomic analysis of three HPV+OPSCC tumour datasets, we identified that deletion of LRP1B was enriched in samples that recurred following chemo-radiation. Knockdown using siRNA in four HPV+ cell lines (UWO23, UWO37, UMSCC47 and 93VU147T) resulted in increased proliferation of all cases. CRISPR/Cas9 deletion of LRP1B in the same cell line panel demonstrated increased proliferation, clonogenic growth and migration, as well as resistance to both cisplatin and radiation in LRP1B deleted cells compared to their respective non-targeting control cells. Cell line derived xenograft studies indicated that the LRP1B knockout tumours were more resistant to cisplatin and radiation therapy compared to their controls invivo.Taken together, our work implicates LRP1B deletion as a potential biomarker for identifying treatment resistant HPV+ OPSCC cases.Copyright © 2023. Published by Elsevier Ltd.