RSK2 in Estrogen Receptor Positive (ER+) Breast Cancer

基于内分泌的治疗在降低死亡率方面非常有效，但约25%的患者将取得进展 而在那些患有转移性疾病的人中，只有30%会有反应。因此，极有必要确定 推动雌激素受体α阳性(ER+)乳腺癌和促进侵袭的机制。我们 发现ERα隔离物激活RSK2，一种丝氨酸/苏氨酸蛋白激酶进入细胞核，促进肿瘤发生 转化和侵袭性肿瘤生长。抗雌激素破坏RSK2/ERα复合体，驱动RSK2 进入细胞质，相应减少了肿瘤的生长。我们假设，未能扰乱 RSK2和ERα与内分泌治疗的相互作用导致肿瘤转移。为了支持这一点 RSK2基因特征对浸润性乳腺癌患者的诊断价值 呃α。RSK2促进ER+乳腺癌进展的机制将被确定，并 在患者来源的异种移植物中进行评估(目标1)。我们将测试RSK2是否与三苯氧胺- 耐药ERα突变体使用工程ER+乳腺系驱动转移(目标2)。基于以下物质的RSK抑制剂 母体化合物SL0101将被用来鉴定体内抑制效果更好的化合物 ER+肿瘤生长和转移(目标3)。本建议书中生成的数据将使用 对终点和纵向分析进行适当的统计。一种RSK抑制剂的研制成功 可以显著改善ER+转移性乳腺癌患者的预后。

Endocrine-based therapies have been very effective at reducing mortality but ~ 25% of patients will progress and only 30% of those with metastatic disease will respond. Therefore, there is a tremendous need to identify the mechanisms that drive estrogen receptor alpha positive (ER+) breast cancer and promote invasion. We found that ERα sequesters activated RSK2, a Ser/Thr protein kinase, into the nucleus to promote neoplastic transformation and invasive tumor growth. Anti-estrogens disrupted the RSK2/ERα complex, driving RSK2 into the cytoplasm with corresponding reduced tumor growth. We hypothesize that failure to disrupt the interaction between RSK2 and ERα with endocrine-based therapy leads to metastasis. In support of this hypothesis the RSK2 gene signature stratifies patients with invasive breast cancer based on positivity for ERα. The mechanism by which RSK2 promotes ER+ breast cancer progression will be identified and evaluated in patient-derived xenografts (aim 1). We will test whether RSK2 in complex with a tamoxifen- resistant ERα mutant drives metastasis using engineered ER+ breast lines (aim 2). RSK inhibitors based on the parent compound, SL0101, will be generated to identify compounds with improved in vivo efficacy to inhibit ER+ tumor growth and metastasis (aim 3). Data generated in this proposal will be analyzed using the appropriate statistics for end point and longitudinal analysis. The successful development of a RSK inhibitor could dramatically improve outcomes for patients with ER+ metastatic breast cancer.