National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Mol Med. 2021 Oct 29;27(1):138. doi: 10.1186/s10020-021-00400-5.
ARID1A is a key component of the SWI/SNF chromatin remodeling complexes which is important for the maintaining of biological processes of cells. Recent studies had uncovered the potential role of ARID1A alterations or expression loss in the therapeutic sensitivity of cancers, but the studies in this field requires to be further summarized and discussed. Therefore, we proposed a series of mechanisms related to the resistance to EGFR-TKIs induced by ARID1A alterations or expression loss and the potential therapeutic strategies to overcome the resistance based on published studies. It suggested that ARID1A alterations or expression loss might be the regulators in PI3K/Akt, JAK/STAT and NF-κB signaling pathways which are strongly associated with the resistance to EGFR-TKIs in NSCLC patients harboring sensitive EGFR mutations. Besides, ARID1A alterations or expression loss could lead to the resistance to EGFR-TKIs via a variety of processes during the tumorigenesis and development of cancers, including epithelial to mesenchymal transition, angiogenesis and the inhibition of apoptosis. Based on the potential mechanisms related to ARID1A, we summarized that the small molecular inhibitors targeting ARID1A or PI3K/Akt pathway, the anti-angiogenic therapy and immune checkpoint inhibitors could be used for the supplementary treatment for EGFR-TKIs among NSCLC patients harboring the concomitant alterations of sensitive EGFR mutations and ARID1A.
ARID1A 是 SWI/SNF 染色质重塑复合物的关键组成部分，对于维持细胞的生物学过程很重要。最近的研究揭示了 ARID1A 改变或表达缺失在癌症治疗敏感性中的潜在作用，但该领域的研究需要进一步总结和讨论。因此，我们根据已发表的研究，提出了一系列与 ARID1A 改变或表达缺失诱导的 EGFR-TKIs 耐药相关的机制，以及克服耐药的潜在治疗策略。这表明 ARID1A 改变或表达缺失可能是 PI3K/Akt、JAK/STAT 和 NF-κB 信号通路的调节剂，与携带敏感 EGFR 突变的 NSCLC 患者对 EGFR-TKIs 的耐药性密切相关。此外，ARID1A 改变或表达缺失可能通过癌症发生和发展过程中的多种途径导致对 EGFR-TKIs 的耐药性，包括上皮间质转化、血管生成和细胞凋亡抑制。基于与 ARID1A 相关的潜在机制，我们总结了针对 ARID1A 或 PI3K/Akt 通路的小分子抑制剂、抗血管生成治疗和免疫检查点抑制剂可用于携带敏感 EGFR 突变和 ARID1A 同时改变的 NSCLC 患者的 EGFR-TKIs 辅助治疗。
