《自然》：新的联合疗法有望克服肝癌的耐药性

资讯作者：Netherlands Cancer Institute

编辑翻译：奇奇

本文献于2021年7月发表在国际著名期刊《自然》（Nature）上。来自中国和荷兰的研究人员发现将抗肝癌药物与另一种药物联合使用，可以克服肝癌的耐药性，这为以后的癌症治疗和药物开发提供了新的方向。

肝癌是世界上最为常见的癌症类型之一，尤其是在中国。荷兰癌症研究所和中国上海的研究人员利用CRISPR/Cas技术进行了一项合作研究，该研究发现，如果将一种肝癌药物与另一种药物联合使用，可以克服肝癌对药物的耐药性。

越来越多的癌症药物（称为靶向治疗）可以抑制癌细胞中DNA错误的影响。不幸的是，癌细胞经常会对这些药物产生抗药性。然后它们通过细胞中的另一种信号通路继续分裂。分子癌症研究人员Rene Bernards通过使用CRISPR/Cas等基因技术将所有通路逐一阻断，从而揭示了癌细胞中的通路。

2012年，Bernards首次发现了这些通路中的一种。他想知道，为什么一种特定的药物对一种难以治疗的特定的结肠癌没有作用，而对含有完全相同的DNA突变的黑色素瘤却有效。然后他发现，将第一种药物与第二种药物相结合可以阻断这一途径，这是一项革命性的发现，引领了一种至今全世界还都在使用的延长生命的联合疗法。它还促进了对其他替代信号传导途径的研究，以及针对其他类型癌症的新联合疗法的出现。

Bernards博士和金浩杰博士，以及他们在欧洲和中国的同事们在《自然》杂志上发表了关于肝癌耐药机制的文章。他们发现了为什么乐伐替尼（市场上为数不多的针对肝癌的靶向药物之一）对75%-80%的患者完全没有效果。

研究人员观察发现，干扰物是一种称为EGFR的生长因子受体。一旦使用乐伐替尼，肝癌细胞中的EGFR就被激活，从而刺激细胞分裂。在小鼠模型中，研究人员随后发现，那些从一开始就对乐伐替尼耐药的肿瘤确实激活了EGFR。

但他们也发现，通过将乐伐替尼与另一种抑制表皮生长因子受体(EGFR)的药物吉非替尼联合使用，有可能消除细胞和小鼠的这种耐药性。这是一种已经被用于治疗肺癌的现有药物。

尽管某些生活方式因素导致肝癌发病率增加，但它在西方却相对少见。然而，在非洲和亚洲，由乙型和丙型肝炎引起的肝癌却是一个大问题，世界上与肝癌相关的死亡有一半发生在中国。由于Rene Bernards在博士后金浩杰所在的上海交通大学担任兼职教授，所以他们得以立即在上海东方肝胆外科医院开展首个人体临床研究。仅这家医院就有600张床位供肝癌患者使用。

这项1期概念验证研究涉及了12名先前对乐伐替尼治疗无效且肿瘤中有大量EGFR的患者。12例中有4例肿瘤明显缩小。参与临床研究的病人数现在增加到了30人。之后，还需要进行更大规模的研究，才能将该联合疗法应用于临床。Bernards指出:“这项研究表明，通过组合使用，可以改善现有的药物治疗。吉非替尼的另一个优势是它还未获得专利，因此价格低廉。”

由于癌症是如此复杂且适应强，联合疗法也变得越来越重要。因此，Bernards最近在一篇文章中提出，药剂师在开发药物时应该转向一种涉及药物创新组合的方法。希望新的治疗方法可以更快地用于患者的治疗中，也希望开发出治疗失败率更低的新药物。

英文原文

Smart Combination Therapy for Liver Cancer Tackles Drug Resistance

Liver cancer is one of the most common cancer types worldwide and is especially common in China. A collaborative effort between researchers at the Netherlands Cancer Institute and Shanghai using CRISPR/Cas has led to the discovery that insensitivity to a liver cancer drug can be prevented if it is given in combination with a second drug.

More and more cancer drugs—known as targeted therapy—inhibit the effects of DNA errors in the cancer cell. Unfortunately, cancer cells often are—or become—resistant to these drugs. They then continue to divide via an alternative signaling route in the cell. Molecular cancer researcher Rene Bernards exposes these routes in cancer cellsby blocking all routes off, one by one, using genetic techniques such as CRISPR/Cas.

Bernards first discovered one of these pathways in 2012. He wanted to know why a specific drug did nothing for a particular form of colon cancer that is difficult to treat, while working fine for melanoma involving exactly the same DNA mutation. Then he figured out that combining the first drug with a second blocks this pathway, a revolutionary discovery, which has led to a life-extending combination therapy that is now used worldwide. It also led to a search for other alternative signaling pathways as well as new combination therapies for other types of cancer.

Dr. Bernards, and Dr. Haojie Jin, and their colleagues in Europe and China describe a similar resistance mechanism, in liver cancer in the journal Nature. They discovered why the drug lenvatinib, one of the few targeted drugs on the market for liver cancer, shows no effectat all in 75-80 percent of patients.

The interferer turned out to be EGFR, a growth factor receptor, that—as the researchers observed—is activated in liver cancer cells as soon as the drug lenvatinib is administered, thereby spurring cell division. In mouse models, the researchers then witnessed that precisely those tumors that were resistant to lenvatinib from the start, did indeed activate the EGFR.

But they also discovered that it is possible to override this resistance in cells as well as mice by combining lenvatinib with another drug, gefitinib, which inhibits EGFR. This is anexisting drug that is already being used to treat lung cancer, for example.

Liver cancer is relatively rare in the West, although certain life style factors have led to an increase in its occurrence. In Africa and Asia, however, liver cancer, mainly as a result of hepatitis B and C, is a major problem, and half of the world's deaths related to liver cancer occur in China. Because Rene Bernards holds a part-time chair at Jiao Tong University in Shanghai postdoc Hoajie Jin's home university, they were able to immediately set up an first-in-human clinical study at the Eastern Hepatobiliary Surgery Hospital in Shanghai. This hospital alone has 600 beds for patients with liver cancer.

This phase 1 proof-of-concept study involved twelve patients who previously did not respond to treatment with lenvatinib and who had large amounts of EGFR in their tumor. A significant reduction of the tumor was observed in four of the twelve. The cohort of patients is now being expanded to thirty. After that, larger clinical studies are needed before this combination therapy can be used in the clinic. Bernards notes, “This study shows that it is possible to improve existing drugs by combining them. Another advantage is that gefitinib is off-patent, making it affordable.”

Because cancer is so complex and adapts so rapidly, combination therapies will become increasingly important. Pharmacists should therefore move towards an approach involving smart combinations of drugs when developing medicines, Bernards recently argued in a vision article. Hopefully, that will mean that new therapies can reach patients more quickly, and that promising new drugs will be less likely to fail during development because they do not work, or don't do enough, on their own.

参考文献 

Haojie Jin et al, EGFR activation limits the response of liver cancer to lenvatinib, Nature(2021). DOI:10.1038/s41586-021-03741-7.

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