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

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?