Preventing in vivo resistance to PI3K/AKT/mTOR inhibitors through Mediator kinase inhibition

PI 3 K/AKT/mTOR通路的失调是癌症中最常见的遗传改变之一， 超过三分之一的实体瘤。该通路关键组分（mTOR、PI 3 K、AKT）的抑制剂 已经被开发出来;其中一些已经被批准用于乳腺癌和某些其他恶性肿瘤。 然而，这些抑制剂的益处受到耐药性发展的限制，耐药性的产生或通过以下途径： 途径内的酶变化或通过激活补偿性信号转导途径， 其他的转录变化。抑制转录抗性机制可以重振使用 PI 3 K/AKT/mTOR抑制剂，对许多癌症患者具有潜在的变革性影响。我们建议 联合收割机将PI 3 K/AKT/mTOR抑制剂与选择性抑制CDK 8/19介体激酶的候选药物组合， 转录重编程的调节因子，耐药性出现所需的关键过程。 CDK 8/19抑制剂（CDK 8/19 i）抑制对不同抗癌药物的耐药性的出现。在 在初步研究中，用mTOR处理由PTEN缺陷的乳腺癌细胞形成的异种移植肿瘤， 抑制剂依维莫司。尽管肿瘤生长在最初的7-8周内完全停止，但所有依维莫司治疗的小鼠都没有出现肿瘤生长。 肿瘤随后恢复生长，表明产生了耐药性。当用一种 CDK 8/19 i作为单一药物对肿瘤生长具有适度的影响，当与依维莫司组合时，CDK 8/19 i 在150天的治疗中完全防止了耐药性的发展。预防依维莫司耐药 CDK 8/19 i与依维莫司对两种肿瘤的转录组学效应的抵消有关。 和基质细胞。我们假设我们的选择性CDK 8/19 i临床前候选药物将抑制 不仅对mTOR而且对PI 3 K和AKT抑制剂产生耐药性，延长了 缓解并可能产生治愈。第一阶段SBIR计划将确定CDK 8/19 i是否能阻止 体内对mTOR抑制剂依维莫司、PI 3 K α抑制剂alpelisib和AKT抑制剂产生耐药性 capivasertib，用于雌激素受体（ER）阳性和三阴性乳腺癌。在目标1下，我们将测试 CDK 8/19 i预防体内对依维莫司、alpelisib和capivasertib产生耐药性的能力 在基于细胞系的ER阳性和三阴性乳腺癌异种移植中。免疫组化和 转录组学分析将被用于表征在体内的基于肿瘤和基质的机制。 对PI 3 K/AKT/mTOR抑制剂的抗性，其通过CDK 8/19抑制来预防。根据目标2，我们将 确定CDK 8/19 i是否会阻止体内对依维莫司组合的耐药性的发展 和CDK 8/19 i在ER阳性和三重-ER的不同临床相关的患者来源的异种移植物（PDX）模型中的表达。 阴性乳腺癌。如果CDK 8/19 i阻止了这些模型中体内抗性的出现， 未来的II期研究将扩展到其他PI 3 K/AKT/mTOR抑制剂，在乳腺癌和其他 恶性肿瘤，以确定最佳的药物组合和适应症的临床开发。

Dysregulation of the PI3K/AKT/mTOR pathway is one of the most common genetic alterations in cancer, found in more than one third of all solid tumors. Inhibitors of the key components of this pathway (mTOR, PI3K, AKT) have been developed; some of them have been approved for breast cancer and for certain other malignancies. However, the benefits of these inhibitors are limited by the development of resistance, which arises either through enzymatic changes within the pathway or by the activation of compensatory signal transduction pathways or other transcriptional changes. Suppressing transcriptional resistance mechanisms could revitalize the use of PI3K/AKT/mTOR inhibitors, with a potentially transformative impact for many cancer patients. We propose to combine PI3K/AKT/mTOR inhibitors with a drug candidate that selectively inhibits CDK8/19 Mediator kinase, a regulator of transcriptional reprogramming, the key process required for the emergence of drug resistance. CDK8/19 inhibitors (CDK8/19i) suppress the emergence of resistance to different anticancer drugs. In preliminary studies, xenograft tumors formed by PTEN-deficient breast cancer cells were treated with mTOR inhibitor everolimus. Although tumor growth was fully arrested for the first 7-8 weeks, all the everolimus-treated tumors subsequently resumed their growth, indicating the development of resistance. While treatment with a CDK8/19i as a single agent had a modest effect on tumor growth, when combined with everolimus, the CDK8/19i fully prevented the development of resistance over 150 days of treatment. Prevention of everolimus resistance by the CDK8/19i was associated with the counteraction of transcriptomic effects of everolimus on both tumor and stromal cells. We hypothesize that our selective CDK8/19i preclinical drug candidate will suppress the development of resistance not only to mTOR but also to PI3K and AKT inhibitors, extending the duration of remission and possibly producing cures. This Phase I SBIR program will determine if the CDK8/19i prevents the development of in vivo resistance to mTOR inhibitor everolimus, PI3Kα inhibitor alpelisib, and AKT inhibitor capivasertib, in estrogen receptor (ER)-positive and triple-negative breast cancers. Under Aim 1, we will test the ability of the CDK8/19i to prevent the development of in vivo resistance to everolimus, alpelisib and capivasertib in cell-line based ER-positive and triple-negative breast cancer xenografts. Immunohistochemistry and transcriptomic analysis will be used to characterize the tumor- and stroma-based mechanisms of in vivo resistance to PI3K/AKT/mTOR inhibitors, which are prevented by CDK8/19 inhibition. Under Aim 2, we will determine if the CDK8/19i will prevent the development of in vivo resistance to the combination of everolimus and CDK8/19i in different clinically relevant patient-derived xenograft (PDX) models of ER-positive and triple- negative breast cancers. If the CDK8/19i prevents the emergence of in vivo resistance in these models, the future Phase II studies will be expanded to other PI3K/AKT/mTOR inhibitors, in breast cancer and other malignancies, to identify the best drug combinations and indications for clinical development.