The Regulation of Apoptosis by Cooperative Src and MAPK Signaling in Thyroid Cancer

甲状腺癌中 Src 和 MAPK 信号协同调节细胞凋亡

• 批准号: 10427125
• 负责人: Madison Mariah King Rose
• 金额: $ 3.4万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10427125
• 关键词: Apoptosis; Apoptotic; BCL2L11 gene; BIM Bcl-2-binding protein; BRAF gene; Biosensor; Cancer Patient; Cell Line; Cells; Cessation of life; Clinic; Clinical; Combined Modality Therapy; Dasatinib; Disease; Distant Metastasis; Goals; Growth; In Vitro; Induction of Apoptosis; Injections; MAP Kinase Gene; MAP2K1 gene; MEK inhibition; MEKs; Malignant neoplasm of thyroid; Mass Spectrum Analysis; Measures; Mediating; Mediator of activation protein; Metastasis Induction; Mission; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mutation; National Cancer Institute; Neoplasm Metastasis; PI3K/AKT; PIK3CA gene; PTK2 gene; Papillary thyroid carcinoma; Pathway interactions; Patients; Phase; Phosphoproteins; Phosphorylation; Prognosis; Property; Protein Array; Protein Tyrosine Kinase; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Research; Research Training; Resistance; Role; Science; Signal Induction; Signal Transduction; Site; Solid Neoplasm; Survival Rate; Thyroid Gland; Treatment Efficacy; Tyrosine; Tyrosine Phosphorylation; anaplastic thyroid cancer; anticancer research; antitumor effect; cancer cell; carcinogenesis; cellular engineering; chemotherapeutic agent; chemotherapy; clinically relevant; driver mutation; effective therapy; in vivo; inhibitor; knock-down; mutant; novel; novel therapeutic intervention; overexpression; pro-apoptotic protein; response; response biomarker; src-Family Kinases; success; targeted agent; targeted treatment; treatment response; tumor; tumor growth; tumor heterogeneity; tumor progression; tumorigenesis; tumorigenic

Project Summary/Abstract: Advanced thyroid cancer patients continue to have dismal prognosis and poor survival ratees due to lack of effective therapies. While the MAPK pathway accounts for a majority of the mutations that arise in thyroid cancer (BRAF, RAS, RET/PTC), targeting this pathway has had mixed success in the clinic. The recent approval of a BRAF inhibitor in combination with a MEK1/2 inhibitor for anaplastic thyroid cancer patients (ATC) with a BRAF V600E mutation is monumental, however, this combination is only effective in subset of ATC patients, and is ineffective in BRAF-mutant papillary thyroid cancer (PTC) patients; highlighting the necessity to identify new therapeutic strategies for patients who do not respond to current therapies. Our lab has discovered Src as a clinically relevant target in thyroid cancer and we have demonstrated that Src inhibition with two structurally independent Src inhibitors, dasatinib and saracatinib, inhibits growth, invasion, and metastasis. However, like many single-agent targeted therapies, clinical responses to single-agent Src inhibition has been limited in solid tumors, indicating combination therapies will be necessary. Accordingly, recent studies have shown that the Src inhibitor, dasatinib, in combination with chemotherapeutic agents has clinical benefit, thus supporting the rationale to identify targets that can be co-inhibited with Src. To this end, our lab has demonstrated that co-inhibition of Src and MEK1/2 synergizes to inhibit growth, increase survival, and induce apoptosis in BRAF- and RAS-mutant thyroid cancer cells, while PIK3CA-mutant cells were shown to be resistant to this combination. To begin to decipher mechanism(s) mediating sensitivity in response to combined Src and MEK1/2 inhibition, I used a reverse phase protein array (RPPA) of >400 proteins and phosphoproteins and identified the pro-apoptotic protein, BIM, as a potential mediator of response. Therefore, the goals of my proposal are to determine the regulation of apoptosis by cooperative Src and MAPK signaling in thyroid cancer. Specifically, in Aim 1 I will determine the regulation and role of PI3K/AKT-dependent signaling in mediating the apoptotic response, in Aim 2 I will determine the mechanism(s) of apoptosis regulated by Src and MAPK signaling, and finally in Aim 3, I will determine the role of combined Src and MEK1/2 inhibition on tumor growth, metastasis, and the induction of apoptosis in vivo. This proposal emphasizes a molecular understanding of mechanisms mediating response to Src and MEK1/2 inhibition to develop new strategies to enhance these effects and potential approaches to sensitize resistant tumors. The completion of the proposed research will help the National Cancer Institute fulfill their mission to support cancer research and training in the fundamental sciences.

项目摘要/摘要： 晚期甲状腺癌患者的预后仍然很差，存活率也很低。 有效的治疗方法。虽然MAPK通路是甲状腺中出现的大部分突变的原因 针对这一途径的癌症(BRAF、RAS、RET/PTC)在临床上取得了好坏参半的结果。最近的 BRAF抑制剂与MEK1/2抑制剂联合治疗间变性甲状腺癌 (ATC)具有BRAF V600E突变是不朽的，然而，这种组合仅在以下几个子集有效 ATC患者，对BRAF突变的乳头状甲状腺癌(PTC)患者无效；突出显示 有必要为对当前治疗无效的患者确定新的治疗策略。我们的实验室 已经发现Src是甲状腺癌的临床相关靶点，我们已经证明了Src 用两种结构独立的Src抑制剂达沙替尼和萨拉卡替尼抑制生长、侵袭、 和转移。然而，像许多单剂靶向治疗一样，对单剂Src的临床反应 抑制作用仅限于实体肿瘤，这表明联合治疗将是必要的。因此， 最近的研究表明，Src抑制剂达沙替尼与化疗药物联合使用具有 临床益处，从而支持确定可与Src共同抑制的靶点的理论基础。为此， 我们的实验室已经证明，共同抑制Src和MEK1/2协同抑制生长，提高存活率， 并诱导BRAF和RAS突变的甲状腺癌细胞凋亡，而PIK3CA突变的细胞 来抵抗这种结合。开始破译敏感反应的中介机制(S) 结合Src和MEK1/2抑制，我使用了&gt；400蛋白质的反相蛋白质阵列(RPPA)和 并将促凋亡蛋白BIM确定为潜在的反应介体。因此， 我的建议的目标是确定通过合作的Src和MAPK信号对细胞凋亡的调节 在甲状腺癌方面。具体地说，在目标1中，我将确定依赖PI3K/AKT的调节和作用 信号在介导细胞凋亡反应中的作用，在目标2中我将确定细胞凋亡的机制(S) 受Src和MAPK信号调节，最后在目标3中，我将确定组合的Src和MAPK信号转导的作用 MEK1/2在体内抑制肿瘤生长、转移和诱导细胞凋亡。这项建议 强调对调节对Src和MEK1/2抑制的反应的机制的分子理解 开发新的策略来增强这些效应，并开发潜在的方法来敏化耐药肿瘤。这个 拟议研究的完成将帮助国家癌症研究所完成他们的使命，支持 癌症研究和基础科学方面的培训。