Overcoming metastatic resistance to ErbB-targeted therapies

人表皮生长因子受体2（Her 2）在20-25%的乳腺癌中过表达。靶向 使用抗体、激酶抑制剂和抗体-药物缀合物的Her 2改善了患者的结局 患有这种类型的乳腺癌然而，Her 2靶向疗法具有固有的缺点， 和获得性耐药性，导致转移性疾病复发和患者死亡。我们实验室最近的研究 和其他人已经开始确定，驱动转移的机制在癌症中同样重要。 促进对靶向分子疗法的抗性。这些机制大致属于以下过程： 上皮-间质转化（EMT）。然而，药物诱导的相似性和差异性 EMT和由已知的EMT生理介质如TGF-β诱导的EMT仍然定义不清。 因此，拟议研究的总体目标是鉴定和靶向 在转移相关EMT和药物诱导的EMT期间进行类似调节，作为开发治疗的手段 专门针对耐药转移的药物。为此，我们的初步研究比较了 用我们建立的转移模型从Her 2治疗抗性模型产生的表达谱 由TGF-β诱导的EMT特异性驱动。这种方法已经产生了关键的基因， 在细胞生产和传感的替代生长因子途径和细胞外基质。当前 应用集中在成纤维细胞生长因子受体-1（FGFR 1）和成纤维细胞生长因子-2（FGF 2）， 在Her 2治疗抗性和EMT驱动的转移进展中有效上调基因。引导 FGFR 1的过表达已经证实了FGF 2：FGFR 1信号传导轴能够促进对FGF 2：FGFR 1的抗性。 临床上使用的Her 2/EGFR激酶抑制剂拉帕替尼。因此，我们建议的AIM 1将利用几个 分子和遗传学方法来建立负责EMT的转录机制， FGFR 1的表达。该转录网络的成员将在患者肿瘤中进行评估。 样本并与患者结局相关。最近批准的Her 2靶向治疗是抗体- 药物偶联物曲妥珠单抗-美坦新（T-DM 1）。我们观察到T-DM 1产生显著的退化， 建立Her 2+肿瘤，但微小残留病（MRD）仍然可通过生物发光检测， 休眠期最终会长出来，并且对T-DM 1有抗性。在AIM 2中，我们将利用诱导模型 的FGFR表达，以阐明其在T-DM 1耐药MRD的存活和最终生长中的作用。 最后，与我们的合作者一起，我们最近建立了FIIN 4的体内应用， FGFR的共价激酶抑制剂。因此，在AIM 3中，我们将继续使用患者来源的异种移植物 (PDX)Her 2+乳腺癌的研究，以建立利用这种下一代化合物联合 拉帕替尼和T-DM 1这些临床前研究将建立靶向Her 2的联合疗法， FGFR能够根除转移性和原发性乳腺癌。

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.