AKT as a resistance mechanism to cell cycle and endocrine therapies in ER+ breast cancer

AKT 作为 ER 乳腺癌细胞周期和内分泌治疗的耐药机制

• 批准号: 10599693
• 负责人: ANDREA Hope BILD
• 金额: $ 9.33万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599693
• 关键词: 1-Phosphatidylinositol 3-Kinase; AKT Signaling Pathway; AKT inhibition; AKT1 gene; AKT3 gene; Automobile Driving; Biological; Biological Assay; Biological Models; CDK4 gene; Cancer Patient; Cell Cycle; Cell Cycle Inhibition; Cell Line; Cell Proliferation; Cell Survival; Cells; Cellular Stress; Computational Molecular Biology; Data; Death Rate; Diagnosis; Endocrine; Estrogen receptor positive; Evolution; Foundations; Genes; Ligands; Measures; Pathway interactions; Patients; Phenotype; Physiological; Play; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Regimen; Resistance; Resistance development; Resources; Role; Sampling; Signal Transduction; Source; Testing; Therapeutic; Up-Regulation; biobank; cancer cell; cancer therapy; cell growth; computational pipelines; computerized tools; extracellular; hormone therapy; inhibitor; inhibitor therapy; malignant breast neoplasm; neoplastic cell; prevent; receptor; refractory cancer; resistance mechanism; response; treatment response; treatment strategy; tumor

Project Summary/Abstract The manifestation of a cancer resistant state during tumor evolution in response to therapy is not clearly explained by any one phenomenon but is partially attributed to intrinsic and adaptive phenotypic rewiring. Given the dynamic phenotypic switching of resistant cells in response to therapy, detailed examination of the sources of resistance is needed to identify vulnerabilities in the components of these resistance mechanisms. We concentrate on estrogen receptor-positive (ER+) breast cancer, which has one of the highest death rates worldwide. Roughly 30% of patients diagnosed with early-stage ER+ breast cancer develop resistance to initial endocrine and cell cycle inhibition therapy. We identified increased levels of the serine/threonine kinases AKT1 and AKT3 in resistant tumors relative to sensitive in patients with early-stage ER+ breast cancer treated with endocrine and CDK4/6 inhibitor therapy. We further observed increased AKT signaling pathways from BIOCARTA and REACTOME gene sets in resistant tumors during treatment. Thus, we hypothesize that upregulation of AKT is a cell survival component of resistance to endocrine and CDK4/6 therapy in early-stage ER+ breast cancer. At physiological conditions, the phosphatidylinositol-3-kinase (PI3K)/AKT pathway is essential for cell growth and plays a key role in regulating survival during cellular stress, which indicates its importance in cancer cell survival and transition to a resistant state during therapy. We will measure components of the AKT pathway that may modulate AKT expression, identify ligand-receptor relationships originating from cell crosstalk that leads to AKT activation, and the role AKT plays during the phenotypic transition to a resistance state. Our analyses will elucidate the benefits of adding AKT inhibitor treatment to endocrine and cell cycle inhibition on extending tumor response to therapy. Using our biorepository of serial and patient tumor samples and spheroid model system, we will test this hypothesis with the following aims. SA1: Using scRNAseq data from patient cancer cells, we will identify the signaling components driving AKT activity, and its downstream consequences, in resistant cancer tumors. We will identify intracellular or extracellular factors leading to AKT upregulation and its importance in the emergence of a resistant state during endocrine and cell cycle inhibition. SA2: Using spheroid assays with isogenic cell lines sensitive or resistant to ribociclib, or patient tumor cells either sensitive or resistant to cell cycle therapy, we will measure the ability of add-on AKT or PI3K inhibitor therapy to prolong response to cell cycle and endocrine therapy. We will test the degree to which AKT inhibition will prolong cancer cell response to endocrine and cell cycle inhibitor treatments and prevent resistant state transition. These studies will elucidate components important for emerging resistant states, reactivation of the cell cycle, and treatment strategies that will resensitize resistant tumors to endocrine and cell cycle inhibition in patients with ER+ breast cancer.

项目概要/摘要 肿瘤响应治疗而进化过程中抗癌状态的表现尚不清楚 任何一种现象都可以解释，但部分归因于内在和适应性表型重新布线。给定 耐药细胞响应治疗的动态表型转换，详细检查来源 需要了解抵抗力来识别这些抵抗机制的组成部分中的漏洞。我们 专注于雌激素受体阳性 (ER+) 乳腺癌，这是死亡率最高的乳腺癌之一 全世界。大约 30% 被诊断为早期 ER+ 乳腺癌的患者对初始治疗产生耐药性 内分泌和细胞周期抑制疗法。我们发现丝氨酸/苏氨酸激酶 AKT1 水平升高 和 AKT3 在耐药肿瘤中相对于敏感的早期 ER+ 乳腺癌患者 内分泌和CDK4/6抑制剂治疗。我们进一步观察到 AKT 信号通路增加 治疗期间耐药肿瘤中的 BIOCARTA 和 REACTOME 基因集。因此，我们假设 AKT 上调是早期内分泌和 CDK4/6 治疗耐药的细胞存活组成部分 ER+乳腺癌。在生理条件下，磷脂酰肌醇-3-激酶 (PI3K)/AKT 途径是 对于细胞生长至关重要，并在细胞应激期间调节生存中发挥关键作用，这表明它 在治疗过程中癌细胞存活和向耐药状态转变的重要性。 我们将测量 AKT 通路中可能调节 AKT 表达的成分，识别配体-受体 源于导致 AKT 激活的细胞串扰的关系，以及 AKT 在 表型转变为抗性状态。我们的分析将阐明添加 AKT 抑制剂的好处 内分泌治疗和细胞周期抑制可延长肿瘤对治疗的反应。使用我们的生物样本库 的连续和患者肿瘤样本和球体模型系统，我们将用以下方法检验这一假设 目标。 SA1：使用来自患者癌细胞的 scRNAseq 数据，我们将识别信号传导成分 在耐药癌症肿瘤中驱动 AKT 活性及其下游后果。我们将确定 导致 AKT 上调的细胞内或细胞外因素及其在出现 内分泌和细胞周期抑制期间的抵抗状态。 SA2：使用同基因细胞系的球体测定 对 ribociclib 敏感或耐药，或患者肿瘤细胞对细胞周期疗法敏感或耐药， 我们将测量附加 AKT 或 PI3K 抑制剂疗法延长细胞周期反应的能力， 内分泌治疗。我们将测试 AKT 抑制会在多大程度上延长癌细胞对内分泌的反应 和细胞周期抑制剂治疗并防止耐药状态转变。这些研究将阐明成分 对于新出现的耐药状态、细胞周期的重新激活以及重新敏感的治疗策略非常重要 ER+乳腺癌患者的肿瘤对内分泌和细胞周期抑制具有抵抗力。