PIK3CA(H1047R)- and Her2-initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling.
PIK3CA(H1047R)- and Her2-initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling.
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DOI：
10.1038/onc.2015.377
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发表时间：
2016-06-09
期刊：
影响因子：
8
通讯作者：
Zhao JJ
中科院分区：
文献类型：
--
作者：
Cheng H;Liu P;Ohlson C;Xu E;Symonds L;Isabella A;Muller WJ;Lin NU;Krop IE;Roberts TM;Winer EP;Arteaga CL;Zhao JJ
具有HER2扩增/过表达的人类乳腺癌经常携带PIK3CA突变，并且往往与较差的预后相关。然而，PIK3CA突变在这些乳腺癌的发生和维持中的作用仍然难以捉摸。在本研究中，我们建立了一种从基因上模拟HER2阳性乳腺癌与共存的PIK3CAH1047R的复合小鼠模型。在小鼠乳腺中诱导PIK3CAH1047R的表达，并激活Her2/Neu的结构性表达，可加速乳腺肿瘤的形成，并增强转移潜能。有趣的是，突变体PIK3CA的可诱导表达导致PI3K/AKT信号的强烈激活，而Her2/HER3信号的减弱，这可以被PIK3CAH1047R的去诱导逆转。引人注目的是，虽然这些由Her2+PIK3CAH1047R发起的原发乳腺肿瘤对HER2靶向治疗无效，但所有肿瘤都对致癌基因PIK3CAH1047R的失活有反应，这种情况非常类似于使用专门针对突变的PIK3CA/p110a的高效抑制剂。值得注意的是，这些肿瘤最终恢复了生长，其中一小部分通过代偿性ERK激活而逃脱了对PI3K的依赖，这种激活可以通过联合抑制Her2和MEK来阻止。综上所述，这些结果表明，PIK3CA特异性抑制作为一种单一疗法，然后及时针对MAPK和HER2进行联合治疗，可能是一种针对HER2阳性肿瘤共存的PIK3CA激活突变的有效治疗方法。
Human breast cancers that have HER2 amplification/overexpression frequently carry PIK3CA mutations, and are often associated with a worse prognosis. However, the role of PIK3CA mutations in the initiation and maintenance of these breast cancers remains elusive. In the present study, we generated a compound mouse model that genetically mimics HER2 positive breast cancer with coexisting PIK3CAH1047R. Induction of PIK3CAH1047R expression in mouse mammary glands with constitutive expression of activated Her2/Neu resulted in accelerated mammary tumorigenesis with enhanced metastatic potential. Interestingly, inducible expression of mutant PIK3CA resulted in a robust activation of PI3K/AKT signaling but attenuation of Her2/Her3 signaling, and this can be reversed by deinduction of PIK3CAH1047R expression. Strikingly, while these Her2+ PIK3CAH1047R initiated primary mammary tumors are refractory to HER2-targeted therapy, all tumors responded to inactivation of the oncogenic PIK3CAH1047R, a situation closely mimicking the use of a highly effective inhibitor specifically targeting the mutant PIK3CA/p110a. Notably, these tumors eventually resumed growth, and a fraction of them escaped PI3K dependence by compensatory ERK activation, which can be blocked by combined inhibition of Her2 and MEK. Together, these results suggest that PIK3CA-specific inhibition as a monotherapy followed by combination therapy targeting MAPK and HER2 in a timely manner may be an effective treatment approach against HER2 positive cancers with coexisting PIK3CA-activating mutations.