Elucidating and Leveraging the mTOR Negative Feedback Pathway in Breast Cancer

阐明和利用乳腺癌中的 mTOR 负反馈通路

• 批准号: 10225343
• 负责人: RUTH A. KERI
• 金额: $ 41.08万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225343
• 关键词: Address; Antineoplastic Agents; Breast Cancer Cell; Breast Cancer Model; Breast Cancer therapy; Bypass; CCI-779; Cancer Cell Growth; Cell Survival; Cells; Clinical; Clinical Trials; Communication; Complex; Computing Methodologies; Dasatinib; Data; Dose-Limiting; Drug Targeting; Drug usage; ERBB2 gene; Elements; Epidermal Growth Factor Receptor; Estrogen Receptors; Estrogen receptor positive; FRAP1 gene; Feedback; Focal Adhesion Kinase 1; Focal Adhesions; Future; Gene Proteins; Genetic; Goals; Growth; Human; In Vitro; Individual; Integrins; Knowledge; Lead; Malignant Neoplasms; Mediating; Modeling; Molecular; Molecular Evolution; Molecular Profiling; Mouse Strains; Mutation; Outcome; PI3K/AKT; PTPN12 gene; Pathway interactions; Patient-derived xenograft models of breast cancer; Patients; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Phosphotransferases; Play; Population; Process; Proteins; Proto-Oncogene Proteins c-akt; Receptor Protein-Tyrosine Kinases; Resistance; Role; Signal Pathway; Signal Transduction; Sirolimus; Source; Tamoxifen; Therapeutic; Toxic effect; Translations; Trastuzumab; Woman; Xenograft procedure; cell growth; combat; expectation; improved; improved outcome; in vivo; inhibitor/antagonist; innovation; insight; kinase inhibitor; mTOR Inhibitor; mTOR inhibition; malignant breast neoplasm; mouse model; neoplastic cell; novel; novel strategies; novel therapeutic intervention; patient derived xenograft model; phosphoproteomics; pre-clinical; predicting response; receptor; response; src-Family Kinases; targeted treatment; therapy outcome; therapy resistant; tool; transcriptomics; treatment response; triple-negative invasive breast carcinoma; tumor; tumor growth

PROJECT SUMMARY Targeted therapies have considerably improved survival from many cancers, including breast cancer. A major limitation of such therapies is resistance that occurs as a consequence of the extreme molecular evolution and adaptability of tumor cells. For targeted therapies to achieve their full potential of inducing sustained cures, they must be paired with additional agents that preclude activation of alternative growth and survival pathways. Identifying the most appropriate combinations requires a concerted effort to uncover mechanisms underlying activation of compensatory pathways. The PI3K/AKT/mTOR pathway is commonly activated in breast cancer. This proposal focuses on discovering new intermediaries of this signaling loop that can be targeted to improve the efficacy of mTOR inhibitors. Of the two mTOR complexes, rapalogs inhibit mTORC1 and protein translation. As single agents, rapalogs have limited efficacy in breast cancer, primarily due to feedback activation of AKT and induction of survival signals. Inhibitors of both mTORC1 and mTORC2 also cause AKT activation. Lastly, while dual inhibitors of PI3K and mTOR block this feedback pathway, they suffer from dose- limiting toxicities. These outcomes indicate that strictly targeting PI3K/AKT/mTOR is insufficient. We postulate that discerning the key elements within the negative feedback pathway that extends from mTOR to AKT will reveal novel targetable proteins for impeding rebound activation of AKT in response to mTOR inhibition. This should improve therapeutic outcomes without increasing toxicity. We used a computational method to reveal dasatinib, an inhibitor of Src Family Kinases (SFK) and Abl kinase, as a drug that may be highly synergistic with rapalogs. In breast cancer cells, dasatinib completely blocked the rebound activation of AKT that occurred with the rapalog, rapamycin. These two drugs also synergistically inhibited growth of triple negative breast cancer cells in vitro, and elicited tumor regression in multiple mouse models of breast cancer. These and other data revealed that at least one SFK resides within the pathway leading from mTOR to AKT and suggests that dual mTOR/SFK inhibition may be a novel approach to curtail resistance to mTOR inhibitors. Using phospho- proteomics and transcriptomics, we also found that focal adhesion signaling may be a major gateway for mTOR negative feedback signaling to AKT. We propose three aims to address these possibilities. In Aim 1, we will assess whether simultaneous blockade of SFKs and mTOR inhibits growth of patient derived xenografts of breast cancers as well as tumors that are resistant to current targeted therapies for HER2 and estrogen receptor. In Aim 2, we will interrogate the role of focal adhesion signaling in mediating mTOR feedback with the goal of leveraging this pathway for therapeutic benefit. Lastly, Aim 3 will uncover molecular signatures of resistance to mTOR/SFK inhibitors with the goal of revealing additional signaling inputs that control mTOR negative feedback. Together, these aims represent a comprehensive approach to discerning the molecular interplay between mTOR, elements of focal adhesions, and AKT in dictating tumor cell survival and growth.

项目摘要 靶向治疗大大提高了许多癌症的生存率，包括乳腺癌。一个主要 这种疗法的局限性是由于极端分子进化而产生的抗性， 肿瘤细胞的适应性。为了使靶向治疗充分发挥其诱导持续治愈的潜力， 它们必须与阻止替代生长和存活途径活化的其它试剂配对。 确定最合适的组合需要共同努力，以揭示其背后的机制。 激活代偿通路。PI 3 K/AKT/mTOR通路通常在乳腺癌中被激活。 该建议的重点是发现这个信号循环的新中介，可以有针对性地改善 mTOR抑制剂的功效。在两种mTOR复合物中，雷帕霉素类似物抑制mTORC 1和蛋白质 翻译.作为单一药物，雷帕霉素类似物在乳腺癌中的疗效有限，主要是由于反馈 激活AKT和诱导存活信号。mTORC 1和mTORC 2的抑制剂也可导致AKT activation.最后，虽然PI 3 K和mTOR的双重抑制剂阻断了这种反馈途径，但它们受到剂量- 限制毒性。这些结果表明，严格靶向PI 3 K/AKT/mTOR是不够的。我们推测 识别从mTOR到AKT的负反馈通路中的关键元件， 揭示了新的可靶向蛋白质，用于阻止响应于mTOR抑制的AKT的反弹激活。这 应该改善治疗效果而不增加毒性。我们用一种计算方法来揭示 达沙替尼，Src家族激酶（SFK）和Abl激酶的抑制剂，作为可能具有高度协同作用的药物， 与rapalogs。在乳腺癌细胞中，达沙替尼完全阻断了AKT的反弹激活， 用雷帕霉素这两种药物还协同抑制三阴性乳腺癌的生长， 癌细胞，并在多种乳腺癌小鼠模型中引起肿瘤消退。这些和其他 数据显示至少一种SFK存在于从mTOR到AKT的通路中，并提示， 双重mTOR/SFK抑制可能是减少对mTOR抑制剂的抗性的新方法。使用磷酸- 我们还发现，粘着斑信号可能是一个主要的网关， mTOR负反馈信号传导至AKT。我们提出三个目标来解决这些可能性。目标1： 将评估SFKs和mTOR的同时阻断是否抑制患者来源的异种移植物的生长， 乳腺癌以及对目前的HER 2和雌激素靶向治疗具有抗性的肿瘤 受体的在目标2中，我们将询问粘着斑信号传导在介导mTOR反馈中的作用， 目的是利用这一途径获得治疗益处。最后，目标3将揭示 对mTOR/SFK抑制剂的抗性，目的是揭示控制mTOR的额外信号输入 负反馈总之，这些目标代表了一种全面的方法来辨别分子 mTOR、局灶性粘连的元件和AKT之间的相互作用决定肿瘤细胞存活和生长。

项目成果

Focal Adhesion Kinase Provides a Collateral Vulnerability That Can Be Leveraged to Improve mTORC1 Inhibitor Efficacy.

• DOI: 10.3390/cancers14143374
• 发表时间: 2022-07-11
• 期刊: CANCERS
• 影响因子: 5.2
• 作者: Cuellar-Vite, Leslie;Weber-Bonk, Kristen L.;Abdul-Karim, Fadi W.;Booth, Christine N.;Keri, Ruth A.
• 通讯作者: Keri, Ruth A.