Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
PLoS One. 2022 Dec 8;17(12):e0256788. doi: 10.1371/journal.pone.0256788. eCollection 2022.
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.
致癌激酶抑制剂在临床上的反应短暂，因为它们会产生很高的获得性耐药性。我们之前曾表明，药理学上利用致癌基因诱导的蛋白毒性应激可以作为一种可行的替代致癌基因靶向治疗的方法。在这里，我们对 Her2+乳腺癌细胞用 Her2 抑制剂进行治疗的过程中的转录组、代谢组和蛋白稳定组学的扰动进行了广泛的分析，涵盖了药物反应、耐药性、复发和停药阶段。我们发现，急性 Her2 抑制除了阻断有丝分裂信号外，还会导致葡萄糖摄取显著下降，糖酵解和全球蛋白质合成关闭。在长期治疗中，Her3 的代偿性过表达允许有丝分裂信号通路重新激活，但未能重新启动葡萄糖摄取和糖酵解，导致蛋白毒性内质网应激，从而维持蛋白质合成阻断和生长抑制。由于 eIF2 磷酸酶 GADD34 的过表达，Her3 介导的内质网应激下的细胞增殖在长期 Her2 抑制下得以实现，该蛋白将蛋白质合成阻断与内质网应激反应解耦联，从而允许细胞活跃生长。我们表明，在获得性抗 Her2 治疗耐药性过程中产生的有丝分裂和蛋白稳定信号的失衡，会对内质网质量控制机制的抑制产生特定的易感性。在停药阶段，这种失衡更为明显，此时 Her2 的去抑制会导致下游信号通路的急性激增，并加剧蛋白稳定失衡。因此，致癌激酶抑制剂的获得性耐药机制可能会产生二次脆弱性，可以在临床上加以利用。
