慢性应激激素可促进对在肺癌患者的EGFR抑制剂的抗性

MD安德森research suggests beta blockers may improve treatment response

MD安德森新闻发布2017年11月8日

Elevated levels of chronic stress hormones, such as those produced by psychological distress, may promote resistance to drugs commonly used to treat lung cancer patients with EGFR mutations, according to new research from得克萨斯大学MD安德森癌症中心的大学。临床患者数据的回顾性分析表明，β-阻断剂的药物可减缓或阻止抗药性的发展对EGFR抑制剂。

这项研究乐动体育LDsports中国发表在今天Science Translational Medicine中，用于非小细胞肺癌（NSCLC）细胞系和小鼠模型来发现和验证由应激激素驱动阻力这些疗法，被称为途径EGFR酪氨酸激酶抑制剂（TKI）。

每年约有16万人在美国被诊断患有非小细胞肺癌，大约15000有转移性疾病的EGFR突变，这意味着他们可以从针对EGFR抑制剂受益。

对于这些患者，EGFR抑制剂最初工作良好，但是电阻不可避免地发展，解释John V. Heymach, M.D., Ph.D.，主席胸/头颈部肿瘤内科。这种性有时与其他EGFR突变，称为T790M相关的，但在其他情况下，原因还不是很清楚。

“It is generally accepted that stress is not good for cancer patients, but a cancer diagnosis as well as the necessary treatments can be quite stressful. This data indicates that stress hormones may act directly on tumor cells and promote resistance to therapy,” said Heymach, the study’s senior author. “The concept that beta blockers, which are well-tolerated and inexpensive, may improve responses to EGFR targeting agents is exciting and should be tested clinically."

Researchers had previously identified a connection between EGFR inhibitor resistance and the immune signaling protein IL-6, which is activated by stress hormones. Therefore, the researchers sought to investigate stress hormone signaling as an alternative mechanism driving resistance to EGFR targeted therapies.

The extensive pre-clinical testing was made possible through infrastructure established by MD Anderson’sMoon Shots Program™, a collaborative effort focused on accelerating the development of scientific discoveries into clinical advances that save patients’ lives. The肺癌Moon Shot™, co-led by Heymach, has established several pipelines to repurpose existing drugs and perform large-scale drug screening in cancer cell lines.

In cultured cell lines, the researchers modeled resistance to common EGFR TKIs, which led to increased levels of IL-6. Stress hormones, such as epinephrine and nor-epinephrine, could increase IL-6 levels by binding to β2-adrenergic receptors and activating specific signaling pathways, explained Monique B. Nilsson, Ph.D., senior research scientist and the study’s lead author.

“This means that the same type of receptors that sense stress in other parts of your body, like in the lung and blood vessels, are also on tumor cells and that stress can “activate” these cancer cells as well,” said Nilsson. “Interestingly, the effect of stress hormones on IL-6 induction was most pronounced in NSCLC cells harboring EGFR activating mutations, and our data indicate there is cooperative signaling between mutant EGFR and β2-adrenergic receptors.”

In mice with transplanted EGFR mutant tumor cells, chronic stress accelerated tumor growth. Moreover, activation of β2-adrenergic receptors promoted EGFR inhibitor resistance, and this effect could be reversed with beta blockers or IL-6 inhibition.

Based on their pre-clinical data, the researchers performed retrospective analysis of available patient samples and data from each of the phase 3 ZEST, BATTLE and phase 3 LUX-Lung3 trials.

与表皮生长因子受体抑制剂治疗的患者,高concentrations of IL-6 in pre-treatment plasma samples was associated with significantly worse overall survival (OS) than lower IL-6 levels, 4.8 months and 11.5 months, respectively. Further, patients using beta blockers had lower levels of plasma IL-6 compared with patients not being treated with beta blockers.

对于患者在LUX-Lung3研究中，EGFR抑制剂治疗改善了无进展生存期（PFS）相对于分别单独化疗，具有11.1和6.9个月的中间PFS。对于谁正好是在研究期间接受β受体阻滞剂的病人，EGFR抑制剂提供了一个更大的好处，13.6个月，中位PFS比例仅为2.5化疗，对应于恶化的可能性减少了75％。

The researchers acknowledge the study was limited in its retrospective analysis of clinical data. While those findings are consistent with data from mouse models and NSCLC cell lines, a prospective randomized study is needed for the highest level of proof and to potentially change the standard of care.

“如果β受体阻滞剂做真正减缓或防止resistance to EGFR inhibitors, then we may be able to give these patients an oral drug that is well tolerated and only costs a few cents a day, a major benefit for patients and the field,” said Heymach.

The researchers are planning prospective studies to investigate the use of beta blockers in treating NSCLC patients with EGFR mutations, and hope to carry out these studies in the next few years.

A full list of co-authors on the study can be found with the paper atScience Translational Medicine。

The current study was supported by LUNGevity Foundation; Lung SPORE grant 5 P50 CA070907; Lung Cancer Moon Shot Program; NIH CCSG(CA016672); 1R01 CA190628; Hallman Fund; Bruton Endowed Chair in Tumor Biology; Standing Fund for EGFR inhibitor resistance; the Fox Lung EGFR Inhibitor; and the Rexanna Foundation for Fighting Lung Cancer. Additional support was provided through CA109298 and the American Cancer Society Research Professor award.

MD安德森作者注意以下利益冲突：Heymach已收到酬金和支付阿斯利康和勃林格殷格翰公司咨询并获得研究经费从阿斯利康公司。乐动体育LDsports中国