天津医科大学Jun Chen等研究人员合作发现，全基因组CRISPR-Cas9筛选鉴定出ITGA8在肺腺癌中对阿比维替尼敏感性的作用。2025年1月14日，《中国药理学报》杂志在线发表了这项成果。

研究人员通过使用CRISPR-Cas9全基因组文库筛选，开发了一种新方法，旨在识别能够增强肺腺癌细胞对表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）敏感性的基因。通过这项筛选，研究人员揭示了整合素亚单位α8（ITGA8）是增强肺腺癌对阿比维替尼敏感性的关键基因。值得注意的是，ITGA8的表达在肺腺癌组织中显著低于邻近的正常组织。生物信息学分析揭示，ITGA8与肺腺癌对阿比维替尼的敏感性呈正相关。研究人员展示了ITGA8的下调显著增强了H1975细胞的增殖、迁移和侵袭。相反，ITGA8的过表达则减少了H1975/ABIR细胞的增殖、迁移和侵袭。

此外，研究人员还证明了ITGA8通过减弱下游FAK/SRC/AKT/MAPK信号通路使肺腺癌细胞对EGFR-TKI更敏感。在H1975细胞异种移植小鼠模型中，ITGA8的下调显著增加了肿瘤生长并降低了对阿比维替尼的敏感性，而ITGA8的过表达则显著抑制了肿瘤增殖并增强了对该药物的敏感性。

该表明，ITGA8抑制肺腺癌细胞的增殖、侵袭和迁移，增强了对EGFR-TKI的敏感性，提高了治疗效果，并延缓了获得性耐药的进展。因此，ITGA8为解决EGFR-TKI获得性耐药性提供了一个潜在的治疗候选靶点，具有全新的视角。

研究人员表示，EGFR-TKI的出现改善了EGFR驱动突变的肺癌患者的预后。然而，获得性对EGFR-TKI的耐药性仍然是治疗中的重大挑战。克服耐药性主要集中在基于耐药机制开发下一代靶向疗法，或者通过抑制旁路通路的激活来抑制或逆转耐药性。

附：英文原文

Title: Genome-wide CRISPR-Cas9 screening identifies ITGA8 responsible for abivertinib sensitivity in lung adenocarcinoma

Author: Li, Xuan-guang, Zhu, Guang-sheng, Cao, Pei-jun, Huang, Hua, Chen, Yu-hao, Chen, Chen, Chen, Pei-jie, Wu, Di, Ding, Chen, Zhang, Zi-he, Zhang, Rui-hao, Hu, Zi-xuan, Zhao, Wen-hao, Liu, Ming-hui, Li, Yong-wen, Liu, Hong-yu, Chen, Jun

Issue&Volume: 2025-01-14

Abstract: The emergence of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has improved the prognosis for lung cancer patients with EGFR-driven mutations. However, acquired resistance to EGFR-TKIs poses a significant challenge to the treatment. Overcoming the resistance has primarily focused on developing next-generation targeted therapies based on the molecular mechanisms of resistance or inhibiting the activation of bypass pathways to suppress or reverse the resistance. In this study we developed a novel approach by using CRISPR-Cas9 whole-genome library screening to identify the genes that enhance the sensitivity of lung adenocarcinoma cells to EGFR-TKIs. Through this screening, we revealed integrin subunit alpha 8 (ITGA8) as the key gene that enhanced sensitivity to abivertinib in lung adenocarcinoma. Notably, ITGA8 expression was significantly downregulated in lung adenocarcinoma tissues compared to adjacent normal tissues. Bioinformatics analyses revealed that ITGA8 was positively correlated with the sensitivity of lung adenocarcinoma to abivertinib. We showed that knockdown of ITGA8 significantly enhanced the proliferation, migration and invasion of H1975 cells. Conversely, overexpression of ITGA8 reduced the proliferation migration and invasion of H1975/ABIR cells. Furthermore, we demonstrated that ITGA8 sensitized lung adenocarcinoma cells to EGFR-TKIs by attenuating the downstream FAK/SRC/AKT/MAPK signaling pathway. In H1975 cell xenograft mouse models, knockdown of ITGA8 significantly increased tumor growth and reduced the sensitivity to abivertinib, whereas overexpression of ITGA8 markedly suppressed tumor proliferation and enhanced sensitivity to the drug. This study demonstrates that ITGA8 inhibits the proliferation, invasion and migration of lung adenocarcinoma cells, enhances the sensitivity to EGFR-TKIs, improves treatment efficacy, and delays the progression of acquired resistance. Thus, ITGA8 presents a potential therapeutic candidate for addressing acquired resistance to EGFR-TKIs from a novel perspective.

DOI: 10.1038/s41401-024-01451-0

Source: https://www.nature.com/articles/s41401-024-01451-0