New Potential Cancer Drug Target Discovered

Novel kinase cascade found to regulate cancer growth.

A recent discovery by scientists may soon lead to a number of new cancer drug targets.

In a study conducted by Sanford Burnham Prebys Medical Discovery Institute, a novel kinase cascade that regulates the mTORC1 protein complex was found. mTORC1 is implicated in the control of cancer growth in response to nutrients.

The study provides further insight into the control of mTORC1 activation and brings attention to many new potential drug targets that treat human pathologies linked to mTORC1 deregulation.

“We have found that the phosphorylation of p62, a protein in the mTORC1 complex, is a critical event required to activate mTORC1 in response to amino acids, an environmental cue that signals the presence of sufficient nutrients to ensure cell growth,” said senior author Maria Diaz-Meco, PhD. “Tight regulation of mTORC1 activation is critical for normal cell growth and homeostasis. When the process becomes uncoupled from nutritional status signals, it can promote the progression of multiple pathological processes.”

Scientists have been studying mTOR for decades in the hopes of better understanding cell growth and its relation to cancer proliferation. Researchers want to gain a working knowledge of how mTOR regulates such an essential cell function that impacts metabolism, growth, protein, and organelle recycling, proliferation and survival.

The mTOR gene produces a protein that forms two distinct complexes, mTORC1 and mTORC2. mTORC1 responds to nutrient availability and growth cues.

When activated, mTORC1 leads to protein synthesis and cell growth. Contrarily, mTORC2 responds only to growth factors such as insulin and is more important for overall survival of the cell.

Currently, there are a few FDA approved mTOR inhibitors in place to treat specific cancers, organ transplantation, coronary restenosis, and rheumatoid arthritis. However, since many of the drugs are dual inhibitors of mTORC1 and mTORC2, the drugs can give rise to unwanted and oftentimes life-threatening side effects.

With the discovery of the initiation and control of mTORC1 signaling, scientists will be able to develop newer, more specific, less toxic drug regimens that target this pathway.

“Collectively, we have shown that MEKK3 is the leading kinase in an amino-acid sensing cascade that includes MEK3/6 and p38-delta, and drive p62 phosphorylation, which is a critical step for mTORC1 activation in response to nutrients,” said co-author Jorge Moscat, PhD. “Each of these kinases, MEK3/6, p38-delta and MEKK3, either on their own or in combination, represent a potential target that could selectively modulate mTORC1 activity without inhibiting mTORC2 to potentially treat many human diseases.”

The research from the study demonstrated that p62 is phosphorylated through a cascade that includes 3 tandem kinases: MEKK3, MEK3/6 and p38-delta. P38-delta directly phosphorylates p62 when cancer cells are aware that they have nutrients to grow. P62 then orchestrates the binding of components to create the mTORC1 signaling complex.

In an analysis of prostate cancer specimens, levels of MEKK3, p38-delta and p62 were more highly expressed in aggressive tumors with high Gleason scores.

“Our study has not only identified p62 phosphorylation as the initiating signal, but elucidates the cascade of proteins and kinases involved,” Dr. Diaz-Meco said. “Importantly, since we know that kinases can be inhibited with small-molecules, our findings may lead to new drugs that exclusively target the mTORC1 activation pathway, potentially circumventing the unwanted side effects caused by drug interactions with mTORC2. We have already identified MEKK3 inhibitors and are working to develop these compounds in parallel with screening small-molecule libraries with the Conrad Prebys Center for Chemical Genomics at SBP for inhibitors of MEK3/6 and p38-delta.”