Combined Blockade of Activating ERBB2 Mutations and ER Results in Synthetic Lethality of ER+/HER2 Mutant Breast Cancer.
Combined Blockade of Activating ERBB2 Mutations and ER Results in Synthetic Lethality of ER+/HER2 Mutant Breast Cancer.
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DOI：
10.1158/1078-0432.ccr-18-1544
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发表时间：
2019-01-01
期刊：
影响因子：
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通讯作者：
Arteaga CL
中科院分区：
文献类型：
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作者：
Croessmann S;Formisano L;Kinch LN;Gonzalez-Ericsson PI;Sudhan DR;Nagy RJ;Mathew A;Bernicker EH;Cristofanilli M;He J;Cutler RE Jr;Lalani AS;Miller VA;Lanman RB;Grishin NV;Arteaga CL
我们研究了ERBB2激活突变在雌激素受体阳性(ER+)乳腺癌内分泌治疗抵抗中的作用。从大型基因组数据库中确定ERBB2突变频率。ER+MCF7细胞和异种移植瘤中的等基因敲入ERBB2突变被用来研究雌激素非依赖性生长。通过结构分析确定了HERL755S与HER3的分子相互作用。用小分子和siRNA抑制PI3Kα、TORC1HER3。基因组数据显示，转移性ER+肿瘤的ERBB2突变率高于原发ER+肿瘤。尽管ERα转录活性受到抑制，但携带ERBB2激活域突变的MCF7细胞在体外和体内都表现出对雌激素剥夺和弗维斯特的抵抗。加入不可逆转的HER2酪氨酸激酶抑制剂neratinib恢复了对弗维斯特的敏感性。HER2突变的MCF7细胞比野生型HER2细胞表达更高水平的p-HER3、p-AKT和p-S6。对HER2L755S变异体的结构分析表明，HER2L755S变异体具有更灵活的活性状态，可能允许与HER3增强二聚化。用PI3KMEK抑制剂、α抑制剂或HER3siRNA治疗，但不用MEK抑制剂治疗，恢复了对氟维斯特朗和雌激素剥夺的敏感性。突变型HER2或TORC1的抑制与FUVESTRANT联合应用可有效抑制MCF7/ERBB2V777L移植瘤的生长，提示TORC1在ERBB2突变诱导的抗雌激素耐药中发挥作用。ERBB2突变过度激活HER3/PI3K/AKT/mTOR轴，导致ER+乳腺癌产生抗雌激素耐药。治疗ER+/HER2突变乳腺癌需要双重阻断HER2和ER通路。ER+乳腺癌在抗雌激素治疗进展后，ERBB2激活突变发生的频率增加。用neratinib抑制突变的HER2功能可恢复抗雌激素治疗的效果。因此，我们建议需要双重阻断HER2和ER通路来治疗ER+/HER2突变乳腺癌。
We examined the role of ERBB2 activating mutations in endocrine therapy resistance in estrogen receptor positive (ER+) breast cancer. ERBB2 mutation frequency was determined from large genomic databases. Isogenic knock-in ERBB2 mutations in ER+ MCF7 cells and xenografts were used to investigate estrogen-independent growth. Structural analysis was used to determine the molecular interaction of HERL755S with HER3. Small molecules and siRNAs were used to inhibit PI3Kα, TORC1 and HER3. Genomic data revealed a higher rate of ERBB2 mutations in metastatic vs. primary ER+ tumors. MCF7 cells with isogenically incorporated ERBB2 kinase domain mutations exhibited resistance to estrogen deprivation and to fulvestrant both in vitro and in vivo, despite maintaining inhibition of ERα transcriptional activity. Addition of the irreversible HER2 tyrosine kinase inhibitor neratinib restored sensitivity to fulvestrant. HER2-mutant MCF7 cells expressed higher levels of p-HER3, p-AKT and p-S6 than cells with wild type HER2. Structural analysis of the HER2L755S variant implicated a more flexible active state, potentially allowing for enhanced dimerization with HER3. Treatment with a PI3Kα inhibitor, a TORC1 inhibitor or HER3 siRNA, but not a MEK inhibitor, restored sensitivity to fulvestrant and to estrogen deprivation. Inhibition of mutant HER2 or TORC1, when combined with fulvestrant, equipotently inhibited growth of MCF7/ERBB2V777L xenografts, suggesting a role for TORC1 in antiestrogen resistance induced by ERBB2 mutations. ERBB2 mutations hyperactivate the HER3/PI3K/AKT/mTOR axis, leading to antiestrogen resistance in ER+ breast cancer. Dual blockade of the HER2 and ER pathways is required for the treatment of ER+/HER2 mutant breast cancers. ERBB2 activating mutations occur with increased frequency in ER+ breast cancers after progression on antiestrogen therapy. Inhibition of mutant HER2 function with neratinib restores the efficacy of antiestrogen therapy. Thus, we propose dual blockade of the HER2 and ER pathways is required for the treatment of ER+/HER2 mutant breast cancers.