Targeting YAP-p62 signaling axis suppresses the EGFR-TKI-resistant lung adenocarcinoma.
Targeting YAP-p62 signaling axis suppresses the EGFR-TKI-resistant lung adenocarcinoma.
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DOI：
10.1002/cam4.3734
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发表时间：
2021-03
期刊：
影响因子：
4
通讯作者：
Chung C
中科院分区：
文献类型：
--
作者：
Park HS;Lee DH;Kang DH;Yeo MK;Bae G;Lee D;Yoo G;Kim JO;Moon E;Huh YH;Lee SH;Jo EK;Cho SY;Lee JE;Chung C
尽管先进靶向治疗药物和免疫检查点抑制剂取得了进展，但EGFR-TKI耐药仍然是治疗肺癌的最大障碍之一。自噬抑制剂的临床研究正在积极进行，以克服耐药性。我们使用 PC9、PC9/GR 和 HCC827/GR 细胞系来评估自噬的激活和 EGFR-TKI 耐药性。氯喹用作自噬阻滞剂，维替泊芬用作 YAP 抑制剂。在本研究中，我们试图揭示自噬抑制剂积累的自噬接头p62在EGFR-TKI耐药肺腺癌中的作用。我们发现 p62 具有致癌功能，可诱导 EGFR-TKI 耐药肺腺癌的细胞增殖和侵袭。有趣的是，我们首次发现YAP通过ERK调节p62转录，抑制YAP可以抑制致癌p62的表达。我们还证实p62和YAP的表达在EGFR突变的肺腺癌患者中呈正相关。为了通过干扰 YAP-p62 轴来阻止细胞存活，我们用 YAP 抑制剂维替泊芬治疗 EGFR-TKI 耐药的肺癌细胞。值得注意的是，维替泊芬通过降低具有致癌功能的 p62、YAP 及其靶点 PD-L1 的表达，有效地导致 EGFR-TKI 耐药肺癌细胞死亡。因此，在使用自噬抑制剂时，尤其是作用于自噬末期的药物，如氯喹、巴弗洛霉素A1等，应考虑致癌p62的累积效应。最后，我们建议靶向 YAP-p62 信号轴可用于抑制 EGFR-TKI 耐药肺癌。因此，维替泊芬的药物再利用用于肺癌治疗可能值得考虑，因为它可以同时抑制关键靶标：p62、YAP 和 PD-L1。自噬抑制剂氯喹积累的 p62 在 EGFR-TKI 耐药性肺腺癌中具有致癌功能。 Hippo 效应子 YAP 通过 ERK 调节 p62 转录，抑制 YAP 会显着抑制 p62 的表达。我们认为，靶向 YAP-p62 信号轴可有助于克服肺腺癌中的 EGFR-TKI 耐药性。
Despite the progress of advanced target therapeutic agents and immune checkpoint inhibitors, EGFR‐TKI resistance is still one of the biggest obstacles in treating lung cancer. Clinical studies with autophagy inhibitors are actively underway to overcome drug resistance. We used PC9, PC9/GR, and HCC827/GR cell lines to evaluate the activation of autophagy and EGFR‐TKI resistance. Chloroquine was applied as an autophagic blocker and verteporfin was utilized as a YAP inhibitor. In this study, we tried to reveal the effect of autophagy adaptor p62 which is accumulated by autophagy inhibitor in EGFR‐TKI‐resistant lung adenocarcinoma. We identified that p62 has oncogenic functions that induce cell proliferation and invasion of EGFR‐TKI‐resistant lung adenocarcinoma. Interestingly, we found for the first time that YAP regulates p62 transcription through ERK, and YAP inhibition can suppress the expression of oncogenic p62. We also confirmed that the expressions of p62 and YAP have a positive correlation in EGFR‐mutant lung adenocarcinoma patients. To block cell survival via perturbing YAP‐p62 axis, we treated EGFR‐TKI‐resistant lung cancer cells with YAP inhibitor verteporfin. Remarkably, verteporfin effectively caused the death of EGFR‐TKI‐resistant lung cancer cells by decreasing the expressions of p62 with oncogenic function, YAP, and its target PD‐L1. So, the cumulative effect of oncogenic p62 should be considered when using autophagy inhibitors, especially drugs that act at the last stage of autophagy such as chloroquine and bafilomycin A1. Finally, we suggest that targeting YAP‐p62 signaling axis can be useful to suppress the EGFR‐TKI‐resistant lung cancer. Therefore, drug repurposing of verteporfin for lung cancer treatment may be valuable to consider because it can inhibit critical targets: p62, YAP, and PD‐L1 at the same time. The accumulated p62 by autophagy inhibitor, chloroquine has oncogenic functions in EGFR‐TKI resistant lung adenocarcinoma. Hippo effector YAP regulates p62 transcription through ERK, and YAP inhibition significantly suppresses the expression of p62. We suggest that targeting YAP‐p62 signaling axis can be useful to overcome the EGFR‐TKI resistance in lung adenocarcinoma.
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影响因子：
64.5
作者：
Moscat, Jorge;Karin, Michael;Diaz-Meco, Maria T.
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