Jiang Yuhong, Zhuo Xin, Fu Xiujuan, Wu Yue, Mao Canquan
School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China.
Front Pharmacol. 2021 Apr 22;12:625289. doi: 10.3389/fphar.2021.625289. eCollection 2021.
Drug resistance can notably restrict clinical applications of gefitinib that is a commonly used EGFR-tyrosine kinase inhibitors (EGFR-TKIs) for non-small cell lung cancer (NSCLC). The attempts in exploring novel drug targets and reversal strategies are still needed, since gefitinib resistance has not been fully addressed. Protease-activated receptor 2 (PAR2), a G protein-coupled receptor, possesses a transactivation with EGFR to initiate a variety of intracellular signal transductions, but there is a lack of investigations on the role of PAR2 in gefitinib resistance. This study established that protease-activated receptor 2 (PAR2), actively participated in NSCLC resistant to gefitinib. PAR2 expression was significantly up-regulated when NSCLC cells or tumor tissues became gefitinib resistance. PAR2 inhibition notably enhanced gefitinib to modulate EGFR transactivation, cell viability, migration and apoptosis in gefitinib-sensitive and-resistant NSCLC cells, suggesting its reversal effects in gefitinib resistance. Meanwhile, the combination of a PAR2 inhibitor (P2pal-18S) and gefitinib largely blocked ERK phosphorylation and epithelial-mesenchymal transition (EMT) compared to gefitinib alone. Importantly, we probed its underlying mechanism and uncovered that PAR2 blockade sensitized gefitinib and reversed its resistance mainly via β-arrestin-EGFR-ERK signaling axis. These effects of PAR2 inhibition were further confirmed by the study which showed that P2pal-18S reactivated gefitinib to inhibit tumor growth via restricting ERK activation. Taken together, this study could not only reveal a new mechanism of receptor-mediated transactivation to modulate drug resistance, but also provide a novel drug target and direction for overcoming gefitinib resistance in NSCLC.
耐药性会显著限制吉非替尼的临床应用，吉非替尼是一种常用于治疗非小细胞肺癌（NSCLC）的表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）。由于吉非替尼耐药性问题尚未得到充分解决，仍需探索新的药物靶点和逆转策略。蛋白酶激活受体2（PAR2）是一种G蛋白偶联受体，可与EGFR发生反式激活，启动多种细胞内信号转导，但目前关于PAR2在吉非替尼耐药中的作用尚无研究。本研究证实，蛋白酶激活受体2（PAR2）积极参与NSCLC对吉非替尼的耐药过程。当NSCLC细胞或肿瘤组织对吉非替尼产生耐药时，PAR2表达显著上调。PAR2抑制可显著增强吉非替尼对吉非替尼敏感和耐药NSCLC细胞中EGFR反式激活、细胞活力、迁移和凋亡的调节作用，提示其对吉非替尼耐药具有逆转作用。同时，与单独使用吉非替尼相比，PAR2抑制剂（P2pal-18S）与吉非替尼联合使用可显著阻断ERK磷酸化和上皮-间质转化（EMT）。重要的是，我们探究了其潜在机制，发现PAR2阻断可使吉非替尼敏感化并逆转其耐药性，主要是通过β-抑制蛋白-EGFR-ERK信号轴。PAR2抑制的这些作用在另一项研究中得到进一步证实，该研究表明P2pal-18S可通过限制ERK激活来重新激活吉非替尼以抑制肿瘤生长。综上所述，本研究不仅揭示了受体介导的反式激活调节耐药性的新机制，还为克服NSCLC中吉非替尼耐药性提供了新的药物靶点和方向。
