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

基本信息

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
项目类别：
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

项目摘要

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，每年占52,000多个新诊断。晚期甲状腺甲状腺癌（PTC）和甲状腺甲状腺癌（ATC）是甲状腺癌的侵略性亚型，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，但是，对MAPK导向疗法的耐药性是一个主要问题。作为MAPK途径的最下游节点，ERK1/2的抑制具有减少旁路信号传导和克服电阻的潜力。我已经显示了联合BRAF和ERK抑制阻滞途径重新激活，并抑制体外和体内的生长。此外，我已经表明，BRAF抑制矛盾地增加了在获得的耐药性PTC模型中（长时间缓慢发生的电阻）和内在电阻的ATC模型（前期发生的电阻），该模型被BRAF和ERK的双重抑制阻止。对靶向疗法的耐药性的新兴机制涉及表现出更具侵入性表型的细胞，以存活靶向疗法。我的初步数据表明，BRAF抑制会增加ECM蛋白纤连蛋白（FN1）的表达和分泌。此外，将FN1补充为媒体表型BRAF抑制剂通过增加浸润治疗，这也可以通过抑制ERK来阻止。最后，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入性。综上所述，我假设BRAF抑制作用通过ERK重新激活增加了FN1的产生和分泌，以促进促侵入性自分泌分泌组，从而允许细胞入侵和生存。因此，该提案的目标是：1）确定ERK和FN1在响应BRAF抑制作用中的侵入性表型中的作用，2）确定响应BRAF抑制作用的促侵入性分泌组，并确定3）确定侵入性表型对BRAF抑制体内侵入性表型的作用。预期的结果将确定侵入性表型的关键驱动因素，并将为新颖的治疗策略提供信息，以规避对MAPK的定向疗法的抵抗，并防止侵入和转移。拟议的研究的完成将有助于国家癌症研究所履行其支持基础科学癌症研究和培训的使命。