Treatments involving radiation and chemotherapy alone or in combination have improved patient survival and quality of life. However, cancers frequently evade these therapies due to adaptation and tumor evolution. Given the complexity of predicting response based solely on the initial genetic profile of a patient, a pre-determined treatment course may miss critical adaptation that can cause resistance or induce new targets for drug- and immunotherapy. To address the timescale for these evasive mechanisms, using a mouse xenograft tumor model we investigated the rapidity of gene expression (mRNA), molecular pathway, and phosphoproteome changes after radiation, an HSP90 inhibitor or combination. Animals received radiation, drug or a combination treatment for 1 or 2 weeks and were then euthanized along with a time-matched untreated group for comparison. Changes in gene expression occur as early as 1 week after treatment initiation. Apoptosis and Cell death pathways were activated in irradiated tumor samples. For the HSP90 inhibitor and combination treatment at Week 1 and Week 2 compared to Control Day 1, gene expression changes induced inhibition of pathways including Invasion of cells, Vasculogenesis and Viral infection among others. The combination group included both drug-alone and radiation-alone changes. Our data demonstrates the rapidity of gene expression and functional pathway changes in the evolving tumor as it responds to treatment. Discovering these phenotypic adaptations may help elucidate the challenges in using sustained treatment regimens and could also define evolving targets for therapeutic efficacy.

中文翻译：

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放射线和 HSP90 抑制剂联合治疗后小鼠 FaDu 异种移植肿瘤的分子图谱确定了适应诱导的靶点

单独或联合放疗和化疗的治疗提高了患者的生存率和生活质量。然而，由于适应和肿瘤进化，癌症经常逃避这些治疗。鉴于仅根据患者的初始基因图谱预测反应的复杂性，预先确定的治疗过程可能会错过关键的适应，从而导致耐药性或诱导药物和免疫治疗的新靶点。为了解决这些逃避机制的时间尺度，我们使用小鼠异种移植肿瘤模型研究了放射、HSP90抑制剂或组合后基因表达（mRNA）、分子途径和磷酸化蛋白质组变化的速度。动物接受放射、药物或联合治疗 1 或 2 周，然后与时间匹配的未治疗组一起被安乐死以进行比较。基因表达的变化早在治疗开始后 1 周就会发生。受辐射的肿瘤样本中细胞凋亡和细胞死亡途径被激活。对于第 1 周和第 2 周的 HSP90 抑制剂和联合治疗，与对照第 1 天相比，基因表达变化诱导了对包括细胞侵袭、血管发生和病毒感染等途径的抑制。联合组包括单独药物和单独放射治疗的改变。我们的数据表明，随着肿瘤对治疗的反应，不断发展的肿瘤中基因表达和功能途径发生快速变化。发现这些表型适应可能有助于阐明使用持续治疗方案的挑战，并且还可以定义不断变化的治疗效果目标。