MnSOD-K68-Ac reprograms a lineage plasticity switch / stemness in ER+ breast malignancies.

总结-个性化癌症医学的一个基本主题是确定特定的亚组 基于分子生物标志物和/或肿瘤特征， 新的治疗策略，包括靶向药物。一个重要的，长期的， 这一概念的一个重要方面是乳腺恶性肿瘤的一个亚组对雌激素受体的依赖性 (ER)以及ER信号传导轴。在这方面，有一个亚组的妇女与ER+管腔 B人乳腺恶性肿瘤，由于以下发展而表现出显著的复发风险： 对内分泌治疗的抵抗，包括他莫昔芬。为了解决这个问题， 确定导致内分泌治疗耐药的途径或分子机制。一 癌症医学的第二个重要主题是基于“癌基因成瘾”的想法， 这一现象意味着，虽然肿瘤含有多种遗传，表观遗传，信号传导和代谢， 尽管这种肿瘤的复杂性，细胞的生长和存活往往会受到损害， 单一驱动基因/蛋白质的靶向。 因此，癌基因成瘾现象 在 特定的癌症，包括腔B乳腺癌，提供了一个科学的理由，以确定 致癌的驱动程序的过程中管腔B耐药的内分泌疗法。代谢压力， 由于异常的活性氧ROS水平，是癌症的标志， 导致致癌附加样表型的生理学和代谢，以及对 内分泌治疗基于这些观察，提出K68乙酰化（K68-Ac） 促进一种新发现的MnSOD单体形式，与已建立的ROS不同 四聚MnSOD的解毒作用，重新编程细胞和线粒体代谢， 致癌和肿瘤耐药表型。最后，将针对MnSOD-K68-Ac轴，使用 化学MnSOD模拟物（GC 4419），将内分泌抗性肿瘤转化为敏感表型？

Summary - A fundamental theme in personalized cancer medicine is to identify specific subgroups of patients, based on molecular biomarkers and/or tumor signatures, which will subsequently benefit from new therapeutic strategies, including targeted agents. An important, and longstanding, example of this concept is the dependency of a subgroup of breast malignancies on the estrogen receptor (ER) as well as the ER signaling axis. In this regard, there is a subgroup of women with ER+ luminal B human breast malignancies that exhibit a significant risk of recurrence due to the development of resistance to endocrine therapy, including Tamoxifen. To address this, there is an ongoing search to define the pathways or molecular mechanism(s) leading to the resistance to endocrine therapy. A second significant theme in cancer medicine is based on the idea of “oncogene addiction”, a phenomenon that implies while tumors contain multiple genetic, epigenetic, signaling, and metabolic abnormalities and despite this tumor complexity, cell growth and survival can often be impaired by the targeting of a single driver gene/protein. As such, the phenomenon of oncogene addiction in specific cancers, including luminal B breast carcinogenesis, provides a scientific rational to identify carcinogenic drivers in the process luminal B resistance to endocrine therapies. Metabolic stress, due to aberrant reactive oxygen ROS levels, is a hallmark of cancer that disrupts mitochondrial physiology and metabolism leading to an oncogenic addition-like phenotype and resistance to endocrine therapy. Based on these observations, it is proposed that K68 acetylation (K68-Ac) promotes a newly discovered monomeric form of MnSOD, distinct from the established ROS detoxification role of tetrameric MnSOD, reprograms cellular and mitochondrial metabolism leading to oncogenic and tumor resistance phenotype. Finally, will targeting the MnSOD-K68-Ac axis, using a chemical MnSOD mimic (GC4419), convert endocrine resistance tumors to a sensitive phenotype?