PO.TB03.01 · 肿瘤生物学
抑制促转移激酶网络以治疗耐药性三阴性乳腺癌
Pro-metastatic kinase network inhibition to treat drug-resistant triple-negative breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
转移性三阴性乳腺癌（mTNBC）死亡率高且治疗选择有限。化疗作为mTNBC标准获批治疗的基础，靶向快速分裂的细胞，但无法清除驱动转移的干细胞样细胞。虽然激酶是有前景的药物靶点，但由于肿瘤异质性、耐药性和缺乏预测性生物标志物，单激酶抑制剂在mTNBC中大多无效。我们的策略是识别并靶向促转移肿瘤细胞中的激酶网络，这些网络在耐药细胞中上调或被转移的生理调控因子特异性靶向。我们最初利用这一方法来克服mTNBC中的AKT耐药。采用激酶活性检测（MIB-MS谱分析），我们证明在用AKT抑制剂capivasertib处理患者来源的耐药性mTNBC类器官后，Src家族和ATM/ATR激酶网络上调。序贯给予capivasertib和dasatinib以靶向Src家族并未降低类器官活力，但确实破坏了类器官形成和自我更新，提示有效抑制了转移潜能。在既往工作的基础上，我们随后优化了一种模拟生理性转移抑制因子的多激酶抑制剂方案，靶向关键的应激反应性激酶网络（ERK1/2、p38、JNK和MLK）。这种低剂量药物组合（4MAPKi）既阻止了TNBC转移，又阻止了代偿通路的激活。我们进一步将其精炼为一种三药方案（Ralimetinib、JNK-in-8和Trametinib），可抑制应激激酶网络、促运动性基因表达和类器官实验中的TNBC细胞侵袭。重要的是，将这种抗转移方案与标准化疗联合，使TNBC细胞和类器官对治疗均敏感化。正在进行的研究侧重于用抗体药物偶联物优化治疗疗效、表征针对其他转移调控因子（如转录因子）的特异性激酶网络靶点，以及探索激酶网络作为治疗耐药生物标志物。我们的长期目标是开发一种低毒性、多激酶抑制剂策略，以重编程转移性TNBC细胞，增强其对化疗应答的疗效和持久性，并改善临床结局。
查看英文原文 English abstract
Metastatic triple-negative breast cancer (mTNBC) has high mortality rates and limited therapeutic options. Chemotherapy, the basis of standard approved therapy for mTNBC, targets rapidly dividing cells but fails to eliminate the stem-like cells that drive metastasis. While kinases are promising drug targets, single-kinase inhibitors have been largely ineffective in mTNBC due to tumor heterogeneity, drug resistance, and the absence of predictive biomarkers. Our strategy is to identify and target kinase networks in pro-metastatic tumor cells that are upregulated in drug-resistant cells or specifically targeted by physiological regulators of metastasis. We initially utilized this approach to overcome AKT resistance in mTNBC. Employing a kinase activity assay (MIB-MS profiling), we demonstrated upregulation of Src family and ATM/ATR kinase networks following treatment of patient-derived, drug-resistant mTNBC organoids with the AKT inhibitor capivasertib. Sequential administration of capivasertib and dasatinib to target the Src family did not reduce organoid viability but did disrupt organoid formation and self-renewal, suggesting effective inhibition of metastatic potential. Building on our previous work, we then optimized a multi-kinase inhibitor regimen that mimics a physiological metastasis suppressor by targeting key stress-responsive kinase networks (ERK1/2, p38, JNK, and MLK). This low-dose drug combination (4MAPKi) prevented both TNBC metastasis and activation of compensatory pathways. We further refined this to a three-drug regimen (Ralimetinib, JNK-in-8, and Trametinib) that inhibits stress kinase networks, pro-motility gene expression and TNBC cell invasion in organoid assays. Importantly, combining this antimetastatic regimen with standard chemotherapy sensitized both TNBC cells and organoids to treatment. Ongoing studies focus on optimizing treatment efficacy with antibody-drug conjugates, characterizing kinase network targets specific for other metastasis regulators such as transcription factors, and exploring kinase networks as biomarkers for treatment resistance. Our long-term goal is to develop a low-toxicity, multi-kinase inhibitor strategy that reprograms metastatic TNBC cells, enhancing the efficacy and durability of their response to chemotherapy and improving clinical outcomes.
利益披露 Disclosure
M. Matossian, None..
M. H. Bungert, None..
K. Schechter, None..
M. East, None..
D. O. Okumu, None.
R. Nanda,
AstraZeneca ).
Arvinas ).
BMS ).
Corcept Therapeutics ).
Genentech ).
Gilead ).
GSK ).
Merck ).
Mabwell ).
Novartis ).
OBI Pharma ).
Pfizer ).
Relay ).
Sun Pharma ).
Taiho ).
G. L. Johnson, None..
M. R. Rosner, None.