Editors' ChoiceCancer

Fight fire with fire

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Science Translational Medicine  26 Aug 2015:
Vol. 7, Issue 302, pp. 302ec146
DOI: 10.1126/scitranslmed.aad1823

Human cells employ intricate regulatory networks to promptly adapt the activity of genes in response to control signals. Transcriptional coactivators impact gene activity by reorganizing the transcriptional machinery to simultaneously fine-tune multiple genes. Because coactivators coincidentally affect dozens of cancer-related genes, the consequences of coactivator malfunction are dire. Unrestrained oncogene activity allows cells to escape the safety checkpoints and rush through the cell cycle, leading to genomic instability and cancer. The steroid receptor (SRC) coactivators are frequently amplified in human tumors. If tumor survival requires that the SRC switch is stuck in the “on” position, silencing SRC should selectively kill the coactivator-addicted cancers. With this in mind, Wang et al. embarked on a high-throughput chemical screen for modulators of SRC activity.

The authors identified several SRC inhibitors in an ocean of more than 300,000 candidates but were intrigued by one molecule (MCB-613) in particular, which acted in the opposite way: MCB-613 dramatically boosted SRC activity in gene reporter assays. At the molecular level, the authors found that the drug bound SRC proteins and augmented SRC interaction with other transcriptional activators such as CBP and CARM1.

Most physicians would be reluctant to prescribe an oncogene-activating drug. However, Wang et al. noted that cancer cells died upon in vitro exposure to MCB-613, whereas healthy cells appeared more resistant. MCB-613–exposed cancer cells suffered from reactive oxygen overload and succumbed to paraptosis, a peculiar kind of stress-related death hallmarked by the ballooning of organelles. Thus, MCB-613 amplified oncogenic signals to the level that cancer cells could not tolerate. Further, MCB-613 arrested growth of human breast cancers transplanted into mice without apparent side effects during the 2 months of therapy. More work is needed to confirm that long-term exposure to MCB-613 does not induce cancer. Nevertheless, killing cancer with its own weapon may provide the opportunity to selectively eradicate neoplastic cells with minimal collateral damage. Other oncogene-activating molecules might deserve a similarly detailed evaluation in preclinical studies.

L. Wang et al., Characterization of a steroid receptor coactivator small molecule stimulator that overstimulates cancer cells and leads to cell stress and death. Cancer Cell 28, 240–252 (2015). [Abstract]

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