Cheng H, Liu P, Ohlson C, Xu E, Symonds L, Isabella A, Muller W J, Lin N U, Krop I E, Roberts T M, Winer E P, Arteaga C L, Zhao J J
Cancer Institute, The Second Hospital of Dalian Medical University, Dalian, China.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Oncogene. 2016 Jun 9;35(23):2961-70. doi: 10.1038/onc.2015.377. Epub 2015 Dec 7.
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 PIK3CA(H1047R). Induction of PIK3CA(H1047R) 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 phosphatidylinositol-3-kinase (PI3K)/AKT signaling but attenuation of Her2/Her3 signaling, and this can be reversed by deinduction of PIK3CA(H1047R) expression. Strikingly, although these Her2(+) PIK3CA(H1047R)-initiated primary mammary tumors are refractory to HER2-targeted therapy, all tumors responded to inactivation of the oncogenic PIK3CA(H1047R), 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.
具有HER2扩增/过表达的人类乳腺癌经常携带PIK3CA突变，且往往与较差的预后相关。然而，PIK3CA突变在这些乳腺癌的起始和维持中的作用仍不清楚。在本研究中，我们构建了一种复合小鼠模型，该模型通过基因手段模拟了同时存在PIK3CA（H1047R）的HER2阳性乳腺癌。在具有组成型激活的Her2/Neu表达的小鼠乳腺中诱导PIK3CA（H1047R）表达，导致乳腺肿瘤发生加速，转移潜能增强。有趣的是，突变型PIK3CA的可诱导表达导致磷脂酰肌醇-3-激酶（PI3K）/AKT信号通路强烈激活，但Her2/Her3信号通路减弱，而这种情况可通过去除PIK3CA（H1047R）表达来逆转。令人惊讶的是，尽管这些Her2（+）PIK3CA（H1047R）引发的原发性乳腺肿瘤对HER2靶向治疗无效，但所有肿瘤对致癌性PIK3CA（H1047R）的失活均有反应，这种情况与使用特异性靶向突变型PIK3CA/p110α的高效抑制剂的情况非常相似。值得注意的是，这些肿瘤最终恢复生长，其中一部分通过补偿性ERK激活逃避了PI3K依赖性，而联合抑制Her2和MEK可阻断这种激活。总之，这些结果表明，PIK3CA特异性抑制作为单一疗法，随后及时进行靶向MAPK和HER2的联合疗法，可能是治疗具有共存PIK3CA激活突变的HER2阳性癌症的有效治疗方法。
