Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, PR China.
Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, PR China.
Biochim Biophys Acta Mol Cell Res. 2022 Jan;1869(1):119144. doi: 10.1016/j.bbamcr.2021.119144. Epub 2021 Sep 30.
Osimertinib, as the third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), is a first-line molecularly targeted drug for non-small cell lung cancer (NSCLC). However, the emergence of therapeutic resistance to osimertinib markedly impairs its efficiency and efficacy, leading to the failure of clinical applications. Novel molecular targets and drugs are urgently needed for reversing osimertinib resistance in NSCLC. Protease-activated receptor 2 (PAR2) that belongs to a subfamily of G protein-coupled receptors can stimulate the transactivation of EGFR to regulate multiple cellular signalling, actively participating in tumour progression. This study firstly discovered that PAR2 expression was notably enhanced when NSCLC cells became resistant to osimertinib. A PAR2 inhibitor facilitated osimertinib to attenuate EGFR transactivation, ERK phosphorylation, EMT and PD-L1 expression which were associated to osimertinib resistance. The combination of the PAR2 inhibitor and osimertinib also notably blocked cell viability, migration, 3D sphere formation and in vivo tumour growth whereas osimertinib itself lost such inhibitory effects in osimertinib-resistant NSCLC cells. Importantly, this reversal effect of PAR2 blockade was uncovered to depend on ERK-mediated EMT and PD-L1, since inhibition of β-arrestin or ERK, which could be modulated by PAR2, sensitized osimertinib to prevent EMT, PD-L1 expression and consequently overcame osimertinib resistance. Thus, this study demonstrated that PAR2 antagonism could limit ERK-mediated EMT and immune checkpoints, consequently attenuating EGFR transactivation and reactivate osimertinib. It suggested that PAR2 may be a novel drug target for osimertinib resistance, and PAR2 inhibition may be a promising strategy candidate for reversing EGFR-TKI resistance in NSCLC.
奥希替尼作为第三代 EGFR 酪氨酸激酶抑制剂（EGFR-TKIs），是治疗非小细胞肺癌（NSCLC）的一线分子靶向药物。然而，奥希替尼治疗耐药的出现显著降低了其疗效，导致临床应用失败。因此，迫切需要寻找新的分子靶点和药物来逆转 NSCLC 中奥希替尼的耐药性。蛋白酶激活受体 2（PAR2）属于 G 蛋白偶联受体亚家族，可刺激 EGFR 的转激活，调节多种细胞信号转导，积极参与肿瘤的进展。本研究首次发现，当 NSCLC 细胞对奥希替尼产生耐药性时，PAR2 的表达明显增强。PAR2 抑制剂促进奥希替尼减弱 EGFR 的转激活、ERK 磷酸化、上皮间质转化（EMT）和 PD-L1 的表达，这些与奥希替尼耐药相关。PAR2 抑制剂与奥希替尼联合应用显著抑制了细胞活力、迁移、3D 球体形成和体内肿瘤生长，而奥希替尼本身在奥希替尼耐药 NSCLC 细胞中失去了这种抑制作用。重要的是，PAR2 阻断的这种逆转作用被揭示依赖于 ERK 介导的 EMT 和 PD-L1，因为 PAR2 可以调节的β-arrestin 或 ERK 的抑制作用，使奥希替尼对 EMT、PD-L1 表达敏感，从而克服奥希替尼耐药性。因此，本研究表明，PAR2 拮抗作用可以限制 ERK 介导的 EMT 和免疫检查点，从而减弱 EGFR 的转激活并重新激活奥希替尼。这表明 PAR2 可能是奥希替尼耐药的一个新的药物靶点，PAR2 抑制可能是逆转 NSCLC 中 EGFR-TKI 耐药的一种有前途的策略候选。
