Oncology Frontier: Are there genes that are associated with resistant endocrine therapy?

　　《肿瘤瞭望》：是否有与内分泌治疗耐药相关的基因？

　　Dr. Ellis: Yes there are genes that are associated with resistance to endocrine therapy， perhaps most notably are estrogen receptors itself. For a long time it was not appreciated how important somatic mutations are in the estrogen receptor to endocrine therapy resistance. The first endocrine therapy resistance mutation in a cancer ever described was a mutation called Y537S. It is a mutation in the ligand binding receptor that causes an abnormal salt bridge causing the estrogen receptor ligand binding pocket to turn into an active confirmation in the absence of ligand. For example， when you treat with an aromatase inhibitor you remove the ligand， that returns the estrogen receptor into an inactive state but now because of this mutation， the estrogen receptor is in an constitutive active confirmation. In 1997， Y537S was described and not a single further example was described until of course we started sequencing metastatic breast cancers and now we find that it is actually quite common. Estrogen receptors are mutant and that is why the endocrine drugs stop working. For example it is the same story in CML， you treat with imatanib and then mutations occur in the kinase domain that prevent the drug being active. You can invent a new drug that activates this despite the mutation and that is the moment we are at actually with endocrine therapy in breast cancer. We also described other translocations in estrogen receptor which actually split the estrogen receptor in half and put on a novel in frame sequence onto estrogen receptor， creating fusion transcription factors which are consistent and again， they do not respond to drug at all because they cannot bind ligand. Unlike the point mutations， the translocations are not even targetable. Typically we see these patients with these translocations having very dramatic history of treatment resistant disease.

　　Ellis博士：是的。确实有与内分泌治疗耐药相关的基因，其中最重要的是ER本身。有很长一段时间，人们不太理解体细胞突变对ER内分泌治疗耐药的重要性。Y537S突变是人类发现的导致癌症内分泌治疗耐药的第一个突变。该突变在配体受体结合时引发盐效应，使ER配体结合袋在无配体的情况下活性构象。例如，在应用芳香化酶抑制剂治疗时若去除配体，可使雌激素受体失活，若存在该突变，则雌激素受体成为活性构象的一部分。1997年，Y537S突变被首次发现，直到我们开始对转移性乳腺癌进行测序，才发现了更多病例。而现在我们知道Y537S突变非常常见的。雌激素受体突变是内分泌治疗耐药的原因所在。这就像慢性粒细胞白血病一样，应用imatanib时若患者在激酶结构域处出现了突变，则药物就无法发生作用。我们可以发明存在突变时仍然具有活性作用的新药，这就是目前内分泌治疗的研究方向。另外，雌激素受体易位可将雌激素受体一分为二，进而激活融合转录因子，使雌激素受体无法与配体结合而导致患者对药物治疗无反应。与点突变不同，这种易位甚至是没有靶向性的。通常情况下，我们会发现这些存在易位的乳腺癌患者都存在严重的治疗耐药病史。