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

研究发现，PI3K/AKT/mTOR通路失调是癌症中最常见的基因改变之一 在超过三分之一的实体肿瘤中。该途径关键成分的抑制剂(mTOR、PI3K、AKT) 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，耐药性是通过以下方式产生的 途径内的酶变化或通过激活代偿信号转导途径或 其他转录变化。抑制转录耐药机制可能会重振对 PI3K/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 将PI3K/AKT/mTOR抑制剂与选择性抑制CDK8/19介导物激酶的候选药物相结合，a 转录重编程的调节，这是出现耐药性所需的关键过程。 CDK8/19抑制剂(CDK8/19i)抑制对不同抗癌药物的耐药性。在……里面 初步研究：用mTOR治疗PTEN缺陷的乳腺癌细胞形成的异种移植瘤 抑制剂伊波利莫斯。尽管肿瘤生长在最初的7-8周内被完全阻止，但所有接受维罗莫司治疗的患者 肿瘤随后恢复生长，表明出现了耐药性。在接受治疗的同时 CDK8/19i作为单独的药物对肿瘤生长的影响不大，当与伊波利马联合使用时，CDK8/19i 经过150天的治疗，完全防止了耐药性的发展。预防埃博利姆耐药性的研究 CDK8/19I与依维莫司对这两种肿瘤的转录抑制作用有关 和基质细胞。我们假设我们的选择性CDK8/19i临床前候选药物将抑制 不仅对mTOR，而且对PI3K和AKT抑制剂产生抗药性，延长了 缓解，并可能产生治愈。此第一阶段SBIR计划将确定CDK8/19i是否阻止 MTOR抑制剂伊维洛莫斯、PI3Kα抑制剂Alpelisib和AKT抑制剂体内耐药性的研究进展 在雌激素受体(ER)阳性和三阴性乳腺癌中，卡皮伐他汀。在目标1下，我们将测试 CDK8/19i预防体内对依维莫司、alpelisib和Capivarertib耐药性的能力 在以细胞系为基础的ER阳性和三阴性乳腺癌移植瘤中。免疫组织化学和 转录分析将被用来表征体内基于肿瘤和基质的机制 对PI3K/AKT/mTOR抑制剂的耐药性，通过抑制CDK8/19来防止。在目标2下，我们将 确定CDK8/19i是否能防止体内对依维莫司联合耐药的发展 和CDK8/19i在不同临床相关患者来源的异种移植模型中的表达 阴性乳腺癌。如果CDK8/19i在这些模型中阻止体内耐药的出现， 未来的第二阶段研究将扩大到其他PI3K/AKT/mTOR抑制剂，用于乳腺癌和其他 恶性肿瘤，以确定临床开发的最佳药物组合和适应症。

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.