The role of an invasive phenotype in promoting resistance to MAPK-directed therapies in thyroid cancer

侵袭性表型在促进甲状腺癌 MAPK 导向疗法耐药性中的作用

• 批准号: 10452508
• 负责人: Hannah M Hicks
• 金额: $ 3.48万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452508
• 关键词: Accounting; Address; BRAF gene; Bypass; Cancer Model; Cancer Patient; Cell Death; Cell Survival; Cells; Cessation of life; Combined Modality Therapy; Data; Diagnosis; Drug resistance; Endocrine; Exhibits; Extracellular Matrix; Extracellular Matrix Proteins; Fibrinogen; Fibronectins; Goals; Growth; Histologic; In Vitro; Injections; Invaded; Location; Longitudinal Studies; MAPK3 gene; Malignant Neoplasms; Malignant neoplasm of thyroid; Mass Spectrum Analysis; Measures; Mission; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; Mutate; Mutation; National Cancer Institute; Neoplasm Metastasis; Outcome; Papillary thyroid carcinoma; Pathway interactions; Patients; Pharmacotherapy; Phenocopy; Phenotype; Prevalence; Primary Neoplasm; Prior Therapy; Production; Proteins; Proteomics; Regulation; Research; Research Training; Resistance; Resort; Role; Salvage Therapy; Science; Signal Transduction; Site-Directed Mutagenesis; Stromal Cells; Stromal Invasion; Supplementation; Therapeutic; Thyroid Gland; Time; Tumor Cell Invasion; Tumor-Derived; anaplastic thyroid cancer; anticancer research; autocrine; cancer cell; combat; genetic approach; in vivo; inhibitor; malignant endocrine gland neoplasm; mutant; new therapeutic target; novel; novel strategies; prevent; resistance mechanism; response; targeted treatment; therapy resistant; treatment strategy; tumor growth

Thyroid cancer is the most common endocrine malignancy, accounting for over 52,000 new diagnoses each year. Advanced papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) are aggressive subtypes of thyroid cancer, and have limited therapeutic options. PTC and ATC are thus the leading causes of endocrine cancer death. Activating mutations of the MAP kinase (MAPK) pathway are common in PTC and ATC, however, drug resistance to MAPK-directed therapies is a major problem. As the most downstream node of the MAPK pathway, inhibition of ERK1/2 has the potential to reduce bypass signaling and overcome resistance. I have shown combined BRAF and ERK inhibition blocks pathway reactivation and inhibits growth in vitro and in vivo. Further, I have shown that BRAF inhibition paradoxically increases invasion in a PTC model of acquired resistance (resistance that occurs slowly over a long period of time) and in ATC models of intrinsic resistance (resistance that occurs upfront), which is blocked by dual inhibition of BRAF and ERK. An emerging mechanism of resistance to targeted therapies involves cells exhibiting a more invasive phenotype to survive targeted therapies. My preliminary data show that BRAF inhibition increases the expression and secretion of the ECM protein fibronectin (FN1). Further, supplementation of FN1 to the media phenocopies BRAF inhibitor treatment by increasing invasion, which can also be blocked by inhibition of ERK. Finally, conditioned media from resistant cells treated with a BRAF inhibitor increases the invasiveness of sensitive cells. Taken together, I hypothesize that BRAF inhibition increases the production and secretion of FN1 through ERK reactivation to promote a pro-invasive autocrine secretome allowing cells to invade and survive. Thus, the goals of this proposal are to 1) determine the role of ERK and FN1 in an invasive phenotype in response to BRAF inhibition, 2) identify the pro-invasive secretome in response to BRAF inhibition, and 3) determine the role of an invasive phenotype in response to BRAF inhibition in vivo. The expected outcomes will identify key drivers of an invasive phenotype and will inform novel treatment strategies to circumvent resistance to MAPK- directed therapies and prevent invasion and metastasis. 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.

甲状腺癌是最常见的内分泌恶性肿瘤，每年有超过52，000例新诊断。晚期乳头状甲状腺癌（PTC）和甲状腺间变性癌（ATC）是甲状腺癌的侵袭性亚型，治疗选择有限。因此，PTC和ATC是内分泌癌死亡的主要原因。MAP激酶（MAPK）途径的激活突变在PTC和ATC中很常见，然而，对MAPK导向疗法的耐药性是一个主要问题。作为MAPK通路的最下游节点，ERK 1/2的抑制具有减少旁路信号传导和克服抗性的潜力。我已经证明了BRAF和ERK的联合抑制阻断了途径的再激活，并在体外和体内抑制了生长。此外，我已经表明，BRAF抑制矛盾地增加了PTC模型的获得性耐药（耐药发生缓慢，在很长一段时间）和ATC模型的内在耐药（耐药发生的前期），这是由BRAF和ERK的双重抑制阻断的入侵。对靶向疗法的抗性的一种新兴机制涉及表现出更具侵袭性表型以在靶向疗法中存活的细胞。我的初步数据显示，BRAF抑制增加ECM蛋白纤连蛋白（FN 1）的表达和分泌。此外，向培养基中补充FN 1通过增加侵袭而模仿BRAF抑制剂处理的表型，这也可以通过抑制ERK来阻断。最后，来自用BRAF抑制剂处理的抗性细胞的条件培养基增加了敏感细胞的侵袭性。综上所述，我假设BRAF抑制通过ERK再激活增加FN 1的产生和分泌，以促进促侵袭自分泌分泌蛋白质组，使细胞侵入和存活。因此，该提议的目标是1）确定ERK和FN 1在响应于BRAF抑制的侵袭性表型中的作用，2）鉴定响应于BRAF抑制的促侵袭性分泌蛋白组，和3）确定体内响应于BRAF抑制的侵袭性表型的作用。预期的结果将确定侵袭性表型的关键驱动因素，并将为新的治疗策略提供信息，以规避对MAPK导向疗法的耐药性并预防侵袭和转移。拟议研究的完成将有助于国家癌症研究所履行其支持癌症研究和基础科学培训的使命。