University Grenoble Alpes, Inserm U1209, CNRS UMR 5309, Team RNA Splicing, Cell Signaling and Response to Therapy, Institute for Advanced Biosciences, Grenoble, France
University Grenoble Alpes, Inserm U1209, CNRS UMR 5309, Team RNA Splicing, Cell Signaling and Response to Therapy, Institute for Advanced Biosciences, Grenoble, France.
Life Sci Alliance. 2024 Oct 1;7(12). doi: 10.26508/lsa.202402873. Print 2024 Dec.
Despite initial high response rates to first-line EGFR TKI, all non-small-cell lung cancer (NSCLC) with EGFR-activating mutation will ultimately develop resistance to treatment. Identification of resistance mechanisms is critical to adapt treatment and improve patient outcomes. Here, we show that a transcript that encodes full-length catalytic subunit 2B of calcineurin accumulates in EGFR-mutant NSCLC cells with acquired resistance against different EGFR TKIs and in post-progression biopsies of NSCLC patients treated with EGFR TKIs. Neutralization of by siRNA or inactivation of calcineurin by cyclosporin A induces apoptosis in resistant cells treated with EGFR TKIs. Mechanistically, EGFR TKIs increase the cytosolic level of calcium and trigger activation of a calcineurin/MEK/ERK pathway that prevents apoptosis. Combining EGFR, calcineurin, and MEK inhibitors overcomes resistance to EGFR TKI in both in vitro and in vivo models. Our results identify PPP3CB overexpression as a new mechanism of acquired resistance to EGFR TKIs, and provide a promising therapeutic approach for NSCLC patients that progress under TKI treatment.
尽管一线 EGFR TKI 最初有很高的应答率，但所有具有 EGFR 激活突变的非小细胞肺癌（NSCLC）最终都会对治疗产生耐药。识别耐药机制对于调整治疗和改善患者预后至关重要。在这里，我们表明，在对不同 EGFR TKI 产生获得性耐药的 EGFR 突变型 NSCLC 细胞中和接受 EGFR TKI 治疗的 NSCLC 患者的进展后活检中，积累了编码完整全长钙调神经磷酸酶 2B 催化亚基 2B 的 转录本。用 siRNA 中和 或用环孢素 A 使钙调神经磷酸酶失活会诱导对 EGFR TKI 耐药的细胞凋亡。在机制上，EGFR TKI 增加细胞质中钙离子的水平，并触发钙调神经磷酸酶/MEK/ERK 通路的激活，从而阻止细胞凋亡。在体外和体内模型中，联合使用 EGFR、钙调神经磷酸酶和 MEK 抑制剂可克服对 EGFR TKI 的耐药性。我们的研究结果确定 PPP3CB 过表达是 EGFR TKI 获得性耐药的新机制，并为接受 TKI 治疗后进展的 NSCLC 患者提供了一种有前途的治疗方法。
