Study Uncovers Mechanism Of Drug Resistance In Form Of Lung Cancer

Susan

http://www.sciencedaily.com/releases/2006/09/060911013810.htm

 

Study Uncovers Mechanism Of Drug Resistance In Form Of Lung Cancer

Science Daily — Dana-Farber Cancer Institute researchers and their colleagues have demonstrated that a genetic error so scarce it can't be detected with some standard screening equipment is often responsible for the loss of effectiveness of front-line drugs against non-small cell lung cancer.

Investigators led by Pasi Jänne, MD, PhD, found that many non-small cell lung cancer (NSCLC) patients who become resistant to targeted drugs such as Iressa® and Tarceva® have a mutation in a single building block of the EGFR protein. The study, which currently is published online by the Journal of Clinical Investigation, demonstrates that even a minute mutation, present in tiny quantities, is sufficient to cause drug resistance in some cancers. The findings will be published in the journal's October print edition.

"The implication of our study is that perhaps many more patients than previously thought have this as their mechanism of resistance," says Jänne. "Identifying those patients will be important in the next generation clinical studies of drugs for NSCLC, which accounts for about 85 percent of all cases of lung cancer in the United States."

Iressa and Tarceva are used to treat NSCLC in patients whose cancer cells have abnormalities in the EGFR gene. It's estimated that 10-15 percent of NSCLC patients in the U.S. have such mutations, and up to 40 percent of those in Asia. In virtually all cases, however, the drugs lose their effectiveness with time -- between six and 14 months, depending on the type of mutation a patient has.

Scientists have suggested that about half of NSCLC patients who develop resistance to Iressa-like drugs have a specific mutation in one of the chemical components of EGFR -- amino acid 790 (designated T790M) -- but it wasn't known whether this secondary mutation was enough to cause the resistance. To find out, Jänne and his colleagues did an experiment involving NSCLC cells from patients who responded well to Iressa. Researchers exposed the cells to Iressa in vitro for six months. As expected, the cells became resistant to the drug. Surprisingly, though, no T790M mutations turned up when the cells were analyzed with standard gene-sequencing techniques.

When researchers used a more sensitive technique, called HPLC (High Performance Liquid Chromatography), which Jänne and his colleagues had previously developed, they found that this cell line did have mutated T790M, but only in a few copies of the gene. Further, they found that the mutated gene -- scarce as it was -- was sufficient to confer Iressa resistance on the cells.

The reason that mutated T790M was so hard to find is because the gene for EGFR was not only mutated in the cells, it was also amplified -- copied in numbers far beyond normal. The amplification basically diluted the evidence, but not the effect, of the T790M mutation.

The investigators also found that in lung cancer patients with EGFR mutations who had become resistant to Iressa, the T790M mutation was not identified by standard gene-sequencing procedures, but by the more advanced HPLC technique.

The discovery offers hope to some NSCLC patients who have relapsed after taking Iressa or Tarceva, remarks Jänne, who is also an assistant professor of medicine at Harvard Medical School.

"Drugs capable of blocking the activity of mutated T790M may be effective therapies in NSCLCs that have become resistant to Iressa and Tarceva. The key is to accurately identify patients who harbor the T790M mutation. Because the mutated gene is present in such small numbers, sophisticated tests like HPLC will be needed to find it," says Jänne. He added that similar challenges in identifying mechanisms of resistance may exist in other malignancies, such as breast cancer, where cancer-gene amplification is common.

Dana-Farber currently is conducting a clinical trial of a novel drug in NSCLC patients who have relapsed from Iressa and have the T790M mutation. "As we're learning to overcome drug resistance in other types of cancer, there is a real possibility we'll be able to make similar progress with this form of NSCLC," explains Jänne.

Jeffrey Engelman, MD, PhD, from Massachusetts General Hospital, is the lead author of the study. The study's co-authors are Toru Mukohara, MD, Kreshnik Zejnullahu, Jason Sun, Sean Tracy, Xiaojun Zhao, PhD, Ana Borras, PhD, and Bruce Johnson, MD, of Dana-Farber; Lewis Cantley, PhD from Beth Israel Deaconess Medical Center; and associates from Children's Hospital Boston and University of Texas M.D. Anderson Cancer Center.

The research was funded in part by grants from the National Institutes of Health and the National Cancer Institute.

今天

Study Uncovers Mechanism Of Drug Resistance In Form Of Lung Cancer

研究揭示肺癌的耐药（药物抗性）机制

Science Daily — Dana-Farber Cancer Institute researchers and their colleagues have demonstrated that a genetic error so scarce it can't be detected with some standard screening equipment is often responsible for the loss of effectiveness of front-line drugs against non-small cell lung cancer.

科学日报—DANA-FARBER癌症学会的研究者和他们的同事证实：一个遗传错误导致用一些标准放映设备无法发现的基因突变使得针对非小细胞肺癌的前线治疗药物失去效果。

Investigators led by Pasi Jänne, MD, PhD, found that many non-small cell lung cancer (NSCLC) patients who become resistant to targeted drugs such as Iressa® and Tarceva® have a mutation in a single building block of the EGFR protein. The study, which currently is published online by the Journal of Clinical Investigation, demonstrates that even a minute mutation, present in tiny quantities, is sufficient to cause drug resistance in some cancers. The findings will be published in the journal's October print edition. 由PASI JANNE带领的调查者们发现很多使用靶向性药物如易瑞莎和他塞瓦耐药性的非小细胞癌患者在单个EGFR的蛋白质有一个突变。该论文近期被临床研究杂志在线发表，其证实即使一个微小的突变，出现很小的数量，也足以导致某些癌症药物耐药。这个发现将在10月份期刊中刊登。

"The implication of our study is that perhaps many more patients than previously thought have this as their mechanism of resistance," says Jänne. "Identifying those patients will be important in the next generation clinical studies of drugs for NSCLC, which accounts for about 85 percent of all cases of lung cancer in the United States."

“我们的研究表明可能比先前更多的患者应该把其作为他们的抵抗机制”，Janne说，辨别那些病人将对下一代临床非小细胞肺癌药物研究有重要意义，在美国非小细胞癌患者约为整个肺癌患者的85%

Iressa and Tarceva are used to treat NSCLC in patients whose cancer cells have abnormalities in the EGFR gene. It's estimated that 10-15 percent of NSCLC patients in the U.S. have such mutations, and up to 40 percent of those in Asia. In virtually all cases, however, the drugs lose their effectiveness with time -- between six and 14 months, depending on the type of mutation a patient has.

易瑞莎和他塞瓦被用来治疗癌细胞有基因突变的非小细胞肺癌患者。据估计约有10-15%的美国非小细胞肺癌患者有这样的突变，在亚洲约有４０％．在所有的案例中，这些药物会在６到１４个月失效，主要取决于这些病人的突变类型．

Scientists have suggested that about half of NSCLC patients who develop resistance to Iressa-like drugs have a specific mutation in one of the chemical components of EGFR -- amino acid 790 (designated T790M) -- but it wasn't known whether this secondary mutation was enough to cause the resistance. To find out, Jänne and his colleagues did an experiment involving NSCLC cells from patients who responded well to Iressa. Researchers exposed the cells to Iressa in vitro for six months. As expected, the cells became resistant to the drug. Surprisingly, though, no T790M mutations turned up when the cells were analyzed with standard gene-sequencing techniques.

科学家们已经建议约有一半的非小细胞癌病人开展阻止类似易瑞莎药物耐药病人在ＥＧＦＲ――氨基酸７９０（称为Ｔ７９０Ｍ）化学成分中出现的特殊突变――但是目前还不知道第二种突变是否足以产生抗药性．为了寻找原因，Janne和他的同事进行了包括易瑞沙药物有效的NSCLC 患者的细胞实验。调查者使用了受益瑞沙影响达到6个月的细胞实验。和预期的一样，这些细胞开始对药物产生抗药。令人惊讶的是，这些细胞在标准基因先后顺序技术中并没有找到T790M的突变。

When researchers used a more sensitive technique, called HPLC (High Performance Liquid Chromatography), which Jänne and his colleagues had previously developed, they found that this cell line did have mutated T790M, but only in a few copies of the gene. Further, they found that the mutated gene -- scarce as it was -- was sufficient to confer Iressa resistance on the cells.

当研究者用更加灵敏的技术，即由ＪＡＮＮＥ和他的同事们先前发展的被称做ＨＰＬＣ（高性能液体染色）的技术，他们发现这个癌细胞线确实有Ｔ７９０变异，但只在一些基因副本里．更进一步的，他们发现这些变异基因虽然稀有，但足以改变易瑞莎在这些细胞上的耐药性。

今天

The reason that mutated T790M was so hard to find is because the gene for EGFR was not only mutated in the cells, it was also amplified -- copied in numbers far beyond normal. The amplification basically dilute the evidence, but not the effect, of the T790M mutation.

Ｔ７９０Ｍ的变异很难发现的原因是由于ＥＧＦＲ基因不只是在细胞里变异，它同时可以被放大－其复制数量大大超过正常水平．这种放大基本稀释了特征，但不是Ｔ７９０Ｍ突变的结果

The investigators also found that in lung cancer patients with EGFR mutations who had become resistant to Iressa, the T790M mutation was not identified by standard gene-sequencing procedures, but by the more advanced HPLC technique.

研究者发现在这些开始出现易瑞莎抗药性的ＥＧＦＲ突变的肺癌患者，Ｔ７９０Ｍ的突变不是被标准的基因顺序程序辨别出来的，而是被更先进的ＨＰＬＣ技术鉴别出来的．

The discovery offers hope to some NSCLC patients who have relapsed after taking Iressa or Tarceva, remarks Jänne, who is also an assistant professor of medicine at Harvard Medical School.

这个发现给予某些服用易瑞莎或者他塞瓦故态复萌的ＮＳＣＬＣ患者带来了希望，身为哈佛医学院药物学助理教授的ＪＡＮＮＥ评论说．

"Drugs capable of blocking the activity of mutated T790M may be effective therapies in NSCLCs that have become resistant to Iressa and Tarceva. The key is to accurately identify patients who harbor the T790M mutation. Because the mutated gene is present in such small numbers, sophisticated tests like HPLC will be needed to find it," says Jänne. He added that similar challenges in identifying mechanisms of resistance may exist in other malignancies, such as breast cancer, where cancer-gene amplification is common.

“能够阻止T790M变异活性的药物可能会有效提高因易瑞莎和他塞瓦耐药的非小细胞肺癌患者的治疗效果。关键的是精确鉴别产生T790M突变的患者。因为变异基因目前数量太少，需要用HPLC这样的精密测试去发现它”，JANNE说。他还指出同样的来自于鉴别抗药机制的挑战还可能存在于其他恶性肿瘤如乳腺癌，其中的癌症基因的扩大也是普遍的。

Dana-Farber currently is conducting a clinical trial of a novel drug in NSCLC patients who have relapsed from Iressa and have the T790M mutation. "As we're learning to overcome drug resistance in other types of cancer, there is a real possibility we'll be able to make similar progress with this form of NSCLC," explains Jänne.

DANNA-FARBER最近在组织一种已服用易瑞莎产生T790突变抗药性的NSCLC的新药的临床实验。Janne解释说：“我们已经学会战胜其他类型的癌症药物抗药性的方法，我们将可能用相同方式取得进展。

Jeffrey Engelman, MD, PhD, from Massachusetts General Hospital, is the lead author of the study. The study's co-authors are Toru Mukohara, MD, Kreshnik Zejnullahu, Jason Sun, Sean Tracy, Xiaojun Zhao, PhD, Ana Borras, PhD, and Bruce Johnson, MD, of Dana-Farber; Lewis Cantley, PhD from Beth Israel Deaconess Medical Center; and associates from Children's Hospital Boston and University of Texas M.D. Anderson Cancer Center.

JERFFREY ENGLELMAN， MD，PHD，是来自马萨诸塞州总医院的该项研究的负责人。这个项目的其他合作者为。。。。。。。。。。。。。。。

The research was funded in part by grants from the National Institutes of Health and the National Cancer Institute.

这项调查得到了国家健康学会和癌症学会的资助和承认．

东方

非常感谢Susan提供的最新信息及今天给我们提供的翻译，希望这项调查能更快的有下文，为我们的亲人提供关键性的帮助。