Drug resistance mechanisms create targetable proteostatic vulnerabilities in Her2+ breast cancers.
Drug resistance mechanisms create targetable proteostatic vulnerabilities in Her2+ breast cancers.
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DOI：
10.1371/journal.pone.0256788
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
Komurov, Kakajan
中科院分区：
文献类型：
--
作者：
Singh, Navneet;Romick-Rosendale, Lindsey;Watanabe-Chailland, Miki;Privette Vinnedge, Lisa M;Komurov, Kakajan
由于获得性耐药率高，致癌激酶抑制剂在临床上表现出短暂的反应。我们以前的研究表明，利用癌基因诱导的蛋白毒性应激可以成为癌基因靶向治疗的一种可行的替代方案。在这里，我们进行了广泛的分析，转录组，代谢组学和蛋白质稳定的扰动过程中的治疗Her2+乳腺癌细胞与Her2抑制剂涵盖药物反应，耐药，复发和药物戒断阶段。我们发现，急性Her2抑制，除了阻断有丝分裂信号，导致葡萄糖摄取的显着下降，糖酵解和全球蛋白质合成的关闭。在长期治疗期间，Her3的代偿性过表达允许促有丝分裂信号通路的重新激活，但未能重新参与葡萄糖摄取和糖酵解，导致蛋白毒性ER应激，其维持蛋白质合成阻断和生长抑制。由于eIF2磷酸酶GADD 34的过表达，在长时间的Her2抑制期间，在ER应激下Her3介导的细胞增殖得以实现，其将蛋白质合成阻断与ER应激反应解偶联，以允许活跃的细胞生长。我们表明，这种不平衡的促有丝分裂和蛋白质抑制信号产生的抗Her2治疗的获得性耐药期间施加了一个特定的脆弱性抑制内质网质量控制机制。后者在药物戒断期更为明显，其中Her2的去抑制在下游信号传导途径中产生急性激增并加剧蛋白质抑制失衡。因此，对致癌激酶抑制剂的获得性耐药机制可能会产生可在临床中利用的继发性漏洞。
Oncogenic kinase inhibitors show short-lived responses in the clinic due to high rate of acquired resistance. We previously showed that pharmacologically exploiting oncogene-induced proteotoxic stress can be a viable alternative to oncogene-targeted therapy. Here, we performed extensive analyses of the transcriptomic, metabolomic and proteostatic perturbations during the course of treatment of Her2+ breast cancer cells with a Her2 inhibitor covering the drug response, resistance, relapse and drug withdrawal phases. We found that acute Her2 inhibition, in addition to blocking mitogenic signaling, leads to significant decline in the glucose uptake, and shutdown of glycolysis and of global protein synthesis. During prolonged therapy, compensatory overexpression of Her3 allows for the reactivation of mitogenic signaling pathways, but fails to re-engage the glucose uptake and glycolysis, resulting in proteotoxic ER stress, which maintains the protein synthesis block and growth inhibition. Her3-mediated cell proliferation under ER stress during prolonged Her2 inhibition is enabled due to the overexpression of the eIF2 phosphatase GADD34, which uncouples protein synthesis block from the ER stress response to allow for active cell growth. We show that this imbalance in the mitogenic and proteostatic signaling created during the acquired resistance to anti-Her2 therapy imposes a specific vulnerability to the inhibition of the endoplasmic reticulum quality control machinery. The latter is more pronounced in the drug withdrawal phase, where the de-inhibition of Her2 creates an acute surge in the downstream signaling pathways and exacerbates the proteostatic imbalance. Therefore, the acquired resistance mechanisms to oncogenic kinase inhibitors may create secondary vulnerabilities that could be exploited in the clinic.