Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface.
Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface.
复制标题
DOI：
10.7554/elife.32271
复制
发表时间：
2018-05-01
期刊：
影响因子：
7.7
通讯作者：
Parker PJ
中科院分区：
文献类型：
--
作者：
Claus J;Patel G;Autore F;Colomba A;Weitsman G;Soliman TN;Roberts S;Zanetti-Domingues LC;Hirsch M;Collu F;George R;Ortiz-Zapater E;Barber PR;Vojnovic B;Yarden Y;Martin-Fernandez ML;Cameron A;Fraternali F;Ng T;Parker PJ
虽然针对HER 2的靶向治疗是HER 2+乳腺癌的有效一线治疗，但获得性耐药仍然是临床挑战。假激酶HER 3是HER 2的异源二聚化伴侣，广泛涉及对HER 2介导的治疗的抗性。在这里，我们表明拉帕替尼，一种ATP竞争性抑制剂的HER 2，是能够诱导增殖合作与HER 3配体neuregulin。抑制剂和生长因子之间的这种违反直觉的协同作用取决于它们促进非典型HER 2-HER 3异源二聚化的能力。通过稳定特定的HER 2构象异构体，拉帕替尼驱动HER 2-HER 3激酶结构域异源复合物的形成。该二聚体以头对头方向存在，不同于典型的不对称活性二聚体。对于这些二聚体观察到的相关聚集倾向于神经调节蛋白反应，提供增殖结果。我们的研究结果提供了机制的见解，涉及的负债与ATP竞争性抑制剂靶向激酶，并强调了复杂的作用，蛋白质构象获得性耐药。大约20%的乳腺癌是由于细胞表面有太多的HER 2受体蛋白拷贝而引起的。HER 2负责告诉细胞分裂。这些受体太多的细胞--乳腺癌细胞的受体数量可能是它们的1000倍--会不受控制地分裂。这导致癌症生长。几种成功的抗癌药物，如Herceptin和Kadcyla，在临床上用于阻断HER 2产生的信号。其他称为激酶抑制剂的药物可以阻止HER 2产生错误信号。然而，一种名为拉帕替尼的激酶抑制剂在临床试验中并不像医学界所希望的那样成功。激酶抑制剂可能具有意想不到的效果。虽然它们可以阻止细胞中的特定信号，但有时也会引起新类型的信号。这可能是拉帕替尼临床试验结果令人失望的原因之一吗？通过对实验室中生长的乳腺癌细胞进行实验，Claus，Patel等人发现拉帕替尼可以违反直觉地促进乳腺癌细胞的生长。这是因为拉帕替尼导致HER 2受体与同一家族的另一种蛋白质受体（称为HER 3）一起聚集在一起，就像沿着的菊花链一样。这些链被启动以快速响应称为神经调节蛋白的分子，神经调节蛋白是一种通常与乳腺癌相关的生长因子。Claus，Patel等人提出的结果表明，一个特定的乳腺癌患者子集-那些癌细胞不增加HER 3受体的产生-可能比其他人更好地响应拉帕替尼。当你试图阻止它时，对HER 2发生了什么的见解也应该影响靶向HER 2或HER 3的新药的设计。
While targeted therapy against HER2 is an effective first-line treatment in HER2+ breast cancer, acquired resistance remains a clinical challenge. The pseudokinase HER3, heterodimerisation partner of HER2, is widely implicated in the resistance to HER2-mediated therapy. Here, we show that lapatinib, an ATP-competitive inhibitor of HER2, is able to induce proliferation cooperatively with the HER3 ligand neuregulin. This counterintuitive synergy between inhibitor and growth factor depends on their ability to promote atypical HER2-HER3 heterodimerisation. By stabilising a particular HER2 conformer, lapatinib drives HER2-HER3 kinase domain heterocomplex formation. This dimer exists in a head-to-head orientation distinct from the canonical asymmetric active dimer. The associated clustering observed for these dimers predisposes to neuregulin responses, affording a proliferative outcome. Our findings provide mechanistic insights into the liabilities involved in targeting kinases with ATP-competitive inhibitors and highlight the complex role of protein conformation in acquired resistance. Around 20% of breast cancers are caused because cells have too many copies of a receptor protein called HER2 on their surface. HER2 is responsible for telling the cell to divide. Cells with too many of these receptors – and breast cancer cells can have up to 1000 times too many – divide uncontrollably. This causes the cancer to grow. Several successful anti-cancer drugs, such as Herceptin and Kadcyla, are used in the clinic to block the signals produced by HER2. Other drugs called kinase inhibitors prevent HER2 from building its faulty signals. However, a particular kinase inhibitor called lapatinib was not as successful in clinical trials as the medical community had hoped. Kinase inhibitors can have unexpected effects. While they can block specific signals in a cell, they can sometimes also cause new types of signals. Could this be one of the reasons behind the disappointing clinical trial results for lapatinib? By performing experiments on breast cancer cells grown in the laboratory, Claus, Patel et al. found that lapatinib can counterintuitively boost the growth of breast cancer cells. This occurs because lapatinib causes HER2 receptors to cluster together like a daisy chain along with another protein receptor of the same family, called HER3. These chains are primed to rapidly respond to a molecule called neuregulin, a growth factor that is commonly associated with breast cancer. The results presented by Claus, Patel et al. indicate that a particular subset of breast cancer patients – those whose cancer cells do not increase production of HER3 receptors – might better respond to lapatinib than others. The insights gained into what happens to HER2 when you try to block it should also influence the design of new drugs that target either HER2 or HER3.