Dual fatty acid synthase and HER2 signaling blockade shows marked antitumor activity against breast cancer models resistant to anti-HER2 drugs.
Dual fatty acid synthase and HER2 signaling blockade shows marked antitumor activity against breast cancer models resistant to anti-HER2 drugs.
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双脂肪酸合酶和HER2信号阻滞显示出针对抗抗HEH2药物的乳腺癌模型的明显抗肿瘤活性。
DOI：
10.1371/journal.pone.0131241
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Puig T
中科院分区：
文献类型：
--
作者：
Blancafort A;Giró-Perafita A;Oliveras G;Palomeras S;Turrado C;Campuzano Ò;Carrión-Salip D;Massaguer A;Brugada R;Palafox M;Gómez-Miragaya J;González-Suárez E;Puig T
阻断脂肪酸合成酶（FATCH）可导致HER 2阳性乳腺癌细胞凋亡。该假设是，阻断FRENZ与抗HER 2信号传导剂组合将是曲妥珠单抗和拉帕替尼耐药的临床前HER 2+乳腺癌模型中的有效抗肿瘤策略。我们开发了对曲妥珠单抗（SKTR）、拉帕替尼（SKLR）和两者（SKLTR）耐药的体外HER 2+模型，并对其进行了分子表征。分析了组合抗FXR多酚化合物（EGCG和合成的G28 UCM）与抗HER 2信号传导药物（曲妥珠单抗加帕妥珠单抗和替西罗莫司）的细胞相互作用。在两种体内正氧代患者中评价了用EGCG、帕妥珠单抗、替西罗莫司或组合治疗后的肿瘤生长抑制：一种来自HER 2+患者，另一种来自基于曲妥珠单抗和拉帕替尼的治疗复发的患者。SKTR、SKLR和SKLTR显示EGFR和p-ERK 1/2和PI 3 KCA突变的过度活化。与单耐药细胞相比，双耐药细胞（SKLTR）也显示出HER 4的过度活化和p-AKT的恢复水平。在SKTR、SKLR和SKLTR中，mTOR、p-mTOR和FXR的表达保持稳定。在体外，抗-Festival化合物加帕妥珠单抗在拉帕替尼和双重抗性细胞中显示协同相互作用，并改善帕妥珠单抗加曲妥珠单抗共同治疗的结果。联合使用替西罗莫司的FRESINE抑制剂在耐药细胞中显示出最强的协同作用。在体内，两种邻苯二甲酸酯对EGCG与帕妥珠单抗或替西罗莫司的组合的抗肿瘤活性显示出强烈的反应，而没有毒性迹象。我们发现，同时阻断FXR和HER 2通路在抗HER 2治疗难治的细胞和乳腺癌模型中是有效的。
Blocking the enzyme Fatty Acid Synthase (FASN) leads to apoptosis of HER2-positive breast carcinoma cells. The hypothesis is that blocking FASN, in combination with anti-HER2 signaling agents, would be an effective antitumor strategy in preclinical HER2+ breast cancer models of trastuzumab and lapatinib resistance. We developed and molecularly characterized in vitro HER2+ models of resistance to trastuzumab (SKTR), lapatinib (SKLR) and both (SKLTR). The cellular interactions of combining anti-FASN polyphenolic compounds (EGCG and the synthetic G28UCM) with anti-HER2 signaling drugs (trastuzumab plus pertuzumab and temsirolimus) were analyzed. Tumor growth inhibition after treatment with EGCG, pertuzumab, temsirolimus or the combination was evaluated in two in vivo orthoxenopatients: one derived from a HER2+ patient and another from a patient who relapsed on trastuzumab and lapatinib-based therapy. SKTR, SKLR and SKLTR showed hyperactivation of EGFR and p-ERK1/2 and PI3KCA mutations. Dual-resistant cells (SKLTR) also showed hyperactivation of HER4 and recovered levels of p-AKT compared with mono-resistant cells. mTOR, p-mTOR and FASN expression remained stable in SKTR, SKLR and SKLTR. In vitro, anti-FASN compounds plus pertuzumab showed synergistic interactions in lapatinib- and dual- resistant cells and improved the results of pertuzumab plus trastuzumab co-treatment. FASN inhibitors combined with temsirolimus displayed the strongest synergistic interactions in resistant cells. In vivo, both orthoxenopatients showed strong response to the antitumor activity of the combination of EGCG with pertuzumab or temsirolimus, without signs of toxicity. We showed that the simultaneous blockade of FASN and HER2 pathways is effective in cells and in breast cancer models refractory to anti-HER2 therapies.
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DOI：
10.1152/ajpregu.00862.2006
发表时间：
2008-02-01
影响因子：
2.8
作者：
Aja, Susan;Landree, Leslie E.;Ronnett, Gabriele V.
通讯作者：
Ronnett, Gabriele V.
影响因子：
9.7
作者：
Gaur, Shikha;Chen, Linling;Yen, Yun
通讯作者：
Yen, Yun
影响因子：
50.3
作者：
Junttila, Teemu T.;Akita, Robert W.;Sliwkowski, Mark X.
通讯作者：
Sliwkowski, Mark X.
DOI：
10.1007/978-0-387-89445-4_2
发表时间：
2009-01-01
期刊：
DRUG RESISTANCE IN CANCER CELLS
影响因子：
--
作者：
Fan, Dominic;Kim, Sun-Jin;Fidler, Isaiah J.
通讯作者：
Fidler, Isaiah J.
影响因子：
3
作者：
Liang, Y.;McDonnell, S.;Clynes, M.
通讯作者：
Clynes, M.