Overcoming metastatic resistance to ErbB-targeted therapies

人表皮生长因子受体2(Her2)在20-25%的乳腺癌中过表达。瞄准 使用抗体、激酶抑制剂和抗体-药物结合物的HER2改善了患者的预后 患有这种亚型的乳腺癌。然而，Her2靶向治疗存在固有的缺陷 和获得性耐药，导致转移性疾病复发和患者死亡。我们实验室最近的研究 其他人已经开始证实，驱动转移的机制在 促进对靶向分子疗法的抵抗力。这些机制大致属于以下进程 上皮-间充质转化(EMT)。然而，药物诱导的异同 EMT和已知的EMT的生理介质，如转化生长因子-β诱导的EMT仍然不清楚。 因此，拟议研究的总体目标是识别和定位以下分子 在转移相关的EMT和药物诱导的EMT中受到类似的调控，作为开发治疗的手段 专门针对耐药转移瘤的药物。为此，我们的初步研究比较了这种基因 我们已建立的转移模型与Her2耐药模型产生的表达谱 它们是由转化生长因子-β诱导的EMT特异性驱动的。这种方法已经产生了涉及到的关键基因 在细胞生产和感知交替的生长因子途径和细胞外基质方面。海流 应用主要集中在成纤维细胞生长因子受体-1(FGFR1)和成纤维细胞生长因子-2(FGF2)，两个 在Her2治疗耐药和EMT驱动的转移进展中都有效地上调了基因。定向 FGFR1的过表达证实了FGF2：FGFR1信号轴能够促进对 临床使用的Her2/EGFR激酶抑制剂拉帕替尼。因此，我们建议的AIM1将利用几个 分子和遗传学方法来建立负责EMT的转录机制- FGFR1的驱动表达。这个转录网络的成员将在患者肿瘤中进行评估 样本，并与患者预后相关。最近批准的Her2靶向治疗是抗体- 药物结合物曲妥珠单抗-恩坦辛(T-DM1)。我们观察T-DM1产生戏剧性的回归 已确诊的Her2+肿瘤，但微小残留病(MRD)仍可通过生物发光及以后检测到 休眠期最终会延长，并对T-DM1产生抵抗力。在AIM2中，我们将使用归纳模型 目的：阐明FGFR在耐T-DM1的MRD细胞存活和最终生长中的作用。 最后，我们与我们的合作者一起，最近建立了FIIN4的体内应用，这是一种新的 FGFR共价激酶抑制剂。因此，在AIM3中，我们将继续使用患者来源的异种移植物 Her2+乳腺癌公司(PDX)联合使用这种下一代化合物建立治疗方法 拉帕替尼和T-DM1。这些临床前研究将建立针对Her2和Her2的联合疗法 FGFR能够根除转移性和原发乳腺癌。

Human Epidermal Growth factor receptor 2 (Her2) is overexpressed in 20-25% of breast cancers. Targeting Her2 using antibodies, kinase inhibitors and antibody-drug conjugates has improved outcomes for patients bearing this subtype of breast cancer. However, Her2-targeted therapies suffer from the drawbacks of inherent and acquired resistance, leading to metastatic disease relapse and patient lethality. Recent studies, by our lab and others have begun to establish that the mechanisms that drive metastasis are similarly essential in facilitating resistance to targeted molecular therapies. These mechanisms broadly fall under the processes of epithelial-mesenchymal transition (EMT). However, the similarities and differences between drug-induced EMT and those induced by known physiologic mediators of EMT, such as TGF-β, remain poorly defined. Therefore, the overall OBJECTIVE of the proposed studies is to identify and target molecules that are similarly regulated during metastasis-associated EMT and drug-induced EMT as a means to develop therapies that specifically target drug resistant metastases. To this end, our preliminary studies have compared the gene expression profiles generated from models of Her2-therapy resistance with our established models of metastasis that are specifically driven by TGF-β-induced EMT. This approach has yielded critical genes that are involved in cellular production and sensing of alternate growth factor pathways and the extracellular matrix. The current application focuses on fibroblast growth factor receptor-1 (FGFR1) and fibroblast growth factor-2 (FGF2), two potently upregulated genes in both Her2-therapy resistance and EMT-driven metastatic progression. Directed overexpression of FGFR1 has validated the FGF2:FGFR1 signaling axis as capable of facilitating resistance to the clinically used Her2/EGFR kinase inhibitor Lapatinib. Therefore, AIM1 of our proposal will utilize several molecular and genetic approaches to establish the transcriptional mechanisms that are responsible for EMT- driven expression of FGFR1. Members of this transcriptional network will be evaluated across patient tumor samples and correlated to patient outcome. The most recently approved Her2-targeted therapy is the antibody- drug conjugate Trastuzumab-emtansine (T-DM1). We observe T-DM1 to produce dramatic regression of established Her2+ tumors, but minimal residual disease (MRD) remains detectable by bioluminescence and after a period of dormancy eventually grows out and is resistant to T-DM1. In AIM2 we will utilize inducible models of FGFR expression to elucidate its role in the survival and eventual outgrowth of T-DM1 resistant MRD. Finally, together with our collaborators we have recently established the in vivo application of FIIN4, a novel covalent kinase inhibitor of FGFR. Therefore, in AIM3 we will continue our use of patient-derived xenografts (PDX) of Her2+ breast cancer to establish therapies utilizing this next-generation compound in combination with Lapatinib and T-DM1. These preclinical studies will establish combination therapies targeting Her2 and FGFR as capable of eradicating metastatic and primary breast cancer.