Closing Down mTOR Signaling Prevents Prostate Tumor Metastasis

An experimental drug the blocks the activity of the molecular pathway moderated by the mTOR (mammalian target of rapamycin) kinase enzyme prevented prostate tumor metastasis in a mouse model of the disease.

mTOR is a master regulator of protein synthesis that under ordinary conditions induces cells to grow and divide. In situations of severe nutrient deprivation, mTOR closes down protein synthesis so that the cell can conserve energy. However, in cancer cells the mTOR pathway misfires and signals tumor cells to grow, divide, undergo metastasis, and invade new, healthy tissues.

Investigators at the University of California, San Francisco (USA) sought to identify the proteins controlled by mTOR signaling in order to understand better how it could be targeted by drugs that would block this activity.

The investigators reported in the February 22, 2012, online edition of the journal Nature that by using an advanced ribosome profiling technique, they had uncovered specialized translation of the prostate cancer genome by oncogenic mTOR signaling, revealing a remarkably specific repertoire of genes involved in cell proliferation, metabolism, and invasion. They extended these findings by functionally characterizing a class of translationally controlled proinvasion messenger RNAs that directed prostate cancer invasion and metastasis downstream of oncogenic mTOR signaling. In addition, they developed a clinically relevant ATP site inhibitor of mTOR, INK128, which reprogrammed this gene expression signature with therapeutic benefit for prostate cancer metastasis.

"We are now discovering that during tumor formation mTOR leads to metastasis by altering the synthesis of a specific group of proteins that make the cancer cells move and invade normal organs,” said senior author Dr. Davide Ruggero, associate professor of urology at the University of California, San Francisco. "Many human cancers show hyperactivation of this pathway. Until now, we have not known how hyperactive mTOR perturbs the synthesis of certain proteins leading to fatal cancer. Deregulations in protein synthesis are now becoming a hallmark of cancer, and we are very excited by the opportunity to target the aberrant protein synthesis apparatus in many cancers."

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