Inhibition of RTK pathways in cancer triggers an adaptive response that promotes therapeutic resistance. Because the adaptive response is multifaceted, the optimal approach to blunting it remains undetermined. TNF upregulation is a biologically significant response to EGFR inhibition in NSCLC. Here, we compared a specific TNF inhibitor (etanercept) to thalidomide and prednisone, two drugs that block TNF and also other inflammatory pathways. Prednisone is significantly more effective in suppressing EGFR inhibition-induced inflammatory signals. Remarkably, prednisone induces a shutdown of bypass RTK signaling and inhibits key resistance signals such as STAT3, YAP and TNF-NF-κB. Combined with EGFR inhibition, prednisone is significantly superior to etanercept or thalidomide in durably suppressing tumor growth in multiple mouse models, indicating that a broad suppression of adaptive signals is more effective than blocking a single component. We identify prednisone as a drug that can effectively inhibit adaptive resistance with acceptable toxicity in NSCLC and other cancers.

抑制癌症中的 RTK 通路会引发适应性反应，从而促进治疗耐药性。由于适应性反应是多方面的，因此抑制它的最佳方法仍未确定。TNF 上调是 NSCLC 中对 EGFR 抑制的生物学显着反应。在这里，我们比较了一种特定的 TNF 抑制剂（依那西普）与沙利度胺和泼尼松，这两种药物可以阻断 TNF 和其他炎症通路。泼尼松在抑制 EGFR 抑制诱导的炎症信号方面明显更有效。值得注意的是，泼尼松诱导旁路 RTK 信号关闭并抑制关键阻力信号，如 STAT3、YAP 和 TNF-NF-κB。结合 EGFR 抑制，泼尼松在多种小鼠模型中持久抑制肿瘤生长方面显着优于依那西普或沙利度胺，表明自适应信号的广泛抑制比阻止单个分量更有效。我们确定泼尼松是一种可以有效抑制 NSCLC 和其他癌症的适应性耐药性且毒性可接受的药物。