The HSP-RTK-Akt axis mediates acquired resistance to Ganetespib in HER2-positive breast cancer.
The HSP-RTK-Akt axis mediates acquired resistance to Ganetespib in HER2-positive breast cancer.
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DOI：
10.1038/s41419-021-03414-3
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发表时间：
2021-01-26
影响因子：
9
通讯作者：
Alexandrova EM
中科院分区：
文献类型：
--
作者：
Eyermann CE;Haley JD;Alexandrova EM
乳腺癌是全世界妇女癌症相关死亡的主要原因。人表皮生长因子受体2（HER 2）阳性亚型占散发性乳腺癌的20%，是一种侵袭性疾病。虽然靶向治疗大大改善了其管理，但原发性和获得性耐药仍然是使其成为可治愈的恶性肿瘤的主要障碍。Ganetespib是一种Hsp 90（热休克蛋白90）小分子抑制剂，在HER 2阳性乳腺癌（包括治疗难治性病例）中显示出优先疗效，并且在正在进行的临床试验中具有极佳的安全性（共38项，其中6项针对乳腺癌）。然而，Ganetespib本身引起获得性耐药性，这是其临床进展的重大障碍。在这里，我们表明Ganetespib在遗传小鼠模型中有效地（尽管是暂时的）抑制HER 2阳性乳腺癌，但动物最终通过获得性耐药性而屈服。我们发现，Ganetespib耐药肿瘤上调几种补偿性HSP，以及广泛的磷酸活化受体酪氨酸激酶（RTK）网络，其中许多是HSP客户。在p-RTK的下游，MAPK通路在耐药肿瘤中仍然受到抑制，HER 2本身也是如此。相比之下，p-RTK效应物Akt是稳定的和磷酸化激活的。值得注意的是，Akt的药理学抑制显著延迟获得性Ganetespib耐药性50%。这些数据将Akt确立为广泛上调的HSP/p-RTK抗性程序下游的统一可操作节点，并表明Akt与Ganetespib共靶向可能是临床中的上级治疗策略。
Breast cancer is the leading cause of cancer-related death in women worldwide. Human epidermal growth factor receptor 2 (HER2)-positive subtype comprises 20% of sporadic breast cancers and is an aggressive disease. While targeted therapies have greatly improved its management, primary and acquired resistance remain a major roadblock to making it a curable malignancy. Ganetespib, an Hsp90 (Heat shock protein 90) small molecule inhibitor, shows preferential efficacy in HER2-positive breast cancer, including therapy-refractory cases, and has an excellent safety profile in ongoing clinical trials (38 in total, six on breast cancer). However, Ganetespib itself evokes acquired resistance, which is a significant obstacle to its clinical advancement. Here, we show that Ganetespib potently, albeit temporarily, suppresses HER2-positive breast cancer in genetic mouse models, but the animals eventually succumb via acquired resistance. We found that Ganetespib-resistant tumors upregulate several compensatory HSPs, as well as a wide network of phospho-activated receptor tyrosine kinases (RTKs), many of which are HSP clients. Downstream of p-RTKs, the MAPK pathway remains suppressed in the resistant tumors, as is HER2 itself. In contrast, the p-RTK effector Akt is stabilized and phospho-activated. Notably, pharmacological inhibition of Akt significantly delays acquired Ganetespib resistance, by 50%. These data establish Akt as a unifying actionable node downstream of the broadly upregulated HSP/p-RTK resistance program and suggests that Akt co-targeting with Ganetespib may be a superior therapeutic strategy in the clinic.
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影响因子：
3.8
作者：
Chien, Amy Jo;Cockerill, Alyson;Munster, Pamela N.
通讯作者：
Munster, Pamela N.
影响因子：
6.4
作者：
Harrison PT;Huang PH
通讯作者：
Huang PH
DOI：
10.1186/s13058-017-0879-5
发表时间：
2017-08-02
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Jhaveri K;Wang R;Teplinsky E;Chandarlapaty S;Solit D;Cadoo K;Speyer J;D'Andrea G;Adams S;Patil S;Haque S;O'Neill T;Friedman K;Esteva FJ;Hudis C;Modi S
通讯作者：
Modi S
影响因子：
7.2
作者：
Biebl, Maximilian M.;Buchner, Johannes
通讯作者：
Buchner, Johannes
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel