2019-07-04 NYC-ATF4

For years, researchers have been trying to target a gene called MYC that is known to drive tumor growth in multiple cancer types when it is mutated or over-expressed, but hitting that target successfully has proven difficult. Now researchers in the Perelman School of Medicine of the University of Pennsylvania have identified a new pathway that works as a partner to MYC and may be its Achilles' Heel. The pathway involves a protein called ATF4, and when it's blocked, it can cause cancer cells to produce too much protein and die. These findings in cell lines and mouse models could point the way toward a new therapeutic approach as inhibitors that can block synthesis of ATF4 already exist. The journal Nature Cell Biology published the findings today.
多年来，研究人员一直试图瞄准一种名为MYC的基因，这种基因已知在突变或过度表达时会驱动多种癌症类型的肿瘤生长，但成功地实现这一目标已被证明是很困难的。现在，宾夕法尼亚大学佩勒曼医学院的研究人员已经确定了一种新的途径，MYC的伙伴，可能是它的致命弱点。这个途径涉及一种叫做ATF 4的蛋白质，当它被阻断时，它会导致癌细胞产生过多的蛋白质而死亡。这些在细胞系和小鼠模型上的发现可以为一种新的治疗方法指明道路，因为抑制剂可以阻止ATF 4的合成。《自然细胞生物学》杂志今天发表了这一发现。

MYC is a gene that controls normal cell growth, but when it is mutated or amplified in cancer, it sets off a chain reaction that helps tumors grow uncontrollably. While there is currently no specific way to target it, previous research has focused on blocking other steps in the chain as a workaround to impede tumor growth. The team, led by Constantinos Koumenis, PhD, the Richard Chamberlain Professor of Radiation Oncology and vice chair and research division director of Radiation Oncology, have previously shown that in certain tumors, one of these steps is regulated by a kinase called PERK, which activates ATF4. However, in this new study, they've shown that blocking PERK does not always stop tumor growth because MYC actually controls a second process that can work in parallel as a redundancy in the system. This study identified this second kinase, which is called GCN2.
MYC是一种控制正常细胞生长的基因，但当它在癌症中发生突变或扩增时，它会引发连锁反应，帮助肿瘤无法控制地生长。虽然目前还没有针对它的具体方法，但之前的研究已经把重点放在阻断链中的其他步骤上，作为阻止肿瘤生长的一种变通方法。由康斯坦丁诺斯·库曼尼斯博士领导的研究小组，是放射肿瘤学理查德·张伯伦教授兼放射肿瘤学副主席和研究部门主任。此前有研究表明，在某些肿瘤中，其中一个步骤是由一种名为PERK的激酶调控的，该激酶激活ATF4。然而，在这项新的研究中，他们已经表明，阻止PERK并不总是能阻止肿瘤的生长，因为MYC实际上控制了第二个过程，这个过程可以作为系统中的冗余并行工作。这项研究发现了第二种激酶，称为GCN2。

"What we've learned is that we need to go further downstream to block tumor growth in a way that cancer cells can't easily escape, and our study identifies the target to do just that," said Koumenis, who is the co-senior author on this study along with Davide Ruggero, PhD, a professor of Urology in the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco (UCSF).
我们学到的是，我们需要走得更远一些，以一种癌细胞无法轻易逃脱的方式阻止肿瘤生长，我们的研究确定了这样做的目标，“库梅尼斯说，他是这项研究的联合高级作者，以及加州大学旧金山分校海伦·迪勒家族综合癌症中心的泌尿学教授戴维斯·拉格罗博士。

This study shows the alternative approach is to target ATF4 itself, since it's the point where both signal pathways converge, meaning there's less redundancy built in to allow cancer to survive. The findings also show that ATF4 turns on the genes MYC needs for growth and also controls the rate at which cells make specific proteins called 4E-BP. When the researchers knocked out ATF4 in cells or mice, they found tumor cells continued to build up those proteins and eventually died as a result of stress. This blocked tumor growth in mice with lymphomas and colorectal cancer. This study also found that when tumors in humans are driven by MYC, ATF4 and its protein partner 4E-BP are also overly expressed, which is further evidence that these findings may point to an approach that could work for humans.
这项研究表明，另一种方法是针对ATF 4本身，因为这是两个信号通路会聚的地方，这意味着存在较少的冗余，从而使癌症得以存活。研究结果还表明，ATF 4启动了MYC生长所需的基因，并控制了细胞产生特定蛋白质的速率，称为4e-BP。当研究人员在细胞或小鼠中敲除ATF 4时，他们发现肿瘤细胞继续积累这些蛋白质，并最终由于压力而死亡。这阻止了淋巴瘤和结直肠癌小鼠的肿瘤生长。这项研究还发现，当人类肿瘤由MYC驱动时，ATF 4及其蛋白伙伴4E-BP也过度表达，这进一步证明了这些发现可能指向了一种对人类有效的方法。

"This shows us the potential impacts of targeting ATF4 in MYC-dependent tumors, something we're already studying. We're also working to confirm this approach will not cause any serious off-target effects," said lead author Feven Tameire, PhD, who conducted this research while she was a doctoral candidate at Penn.
“这向我们展示了靶向ATF 4在MYC依赖性肿瘤中的潜在影响，我们已经在研究这一问题。我们还在努力确认这种方法不会造成任何严重的非目标效应，”第一作者Fven Tameire博士说。她在宾夕法尼亚大学攻读博士学位时进行了这项研究。

Researchers say future studies will also focus on continuing to investigate why ATF4 works the way it does, which may help their understanding of whether there are other potential targets in the chain.
研究人员说，未来的研究也将集中在继续研究为什么ATF 4的工作方式，这可能有助于他们了解链中是否还有其他潜在的目标。