Could there be a brand new way to tackle drug resistance in cancer?
The mechanism involves a previously unknown protein complex called mammalian target of rapamycin complex 3 (mTORC3).
Scientists at St. Jude Children's Research Hospital in Memphis, TN, came across it by chance when they were doing an experiment.
Their study is the subject of a paper that now features in the journal Science Advances.
"This new complex," explains senior study author Gerard C. Grosveld, who is the chair of the genetics department at the hospital, "has not been on anybody's radar screen, even though mTOR complexes have been studied for the last 25 years."
He and his team describe the finding as a "paradigm shift" in our understanding of an important cell growth mechanism and declare that it offers a "novel target for anticancer drug development."
Cell growth regulator
The enzyme mammalian (or mechanistic) target of rapamycin (mTOR) plays a key role in the control of crucial cell processes; it regulates growth and keeps it in a state of equilibrium.
In cancer, abnormal mTOR activation promotes tumor growth. Rapamycin, as well as drugs that act like it — known as rapalogs — are designed to stop this by blocking mTOR.
Most rapalogs, however, have limited effect in cancer because tumor cells are resistant to them.
Scientists had already revealed that mTOR exerted its wide influence from within two large protein complexes: mTORC1 and mTORC2.
Grosveld and his team, however, recently came across evidence to suggest that there might be a third mTOR protein complex, and that a transcription factor protein called ETV7 assembled it.
The experiment that suggested this also revealed that overactive ETV7 was linked to overactive mTOR.
ETV7 assembles mTORC3
By searching through several sources of genomic cancer data, the investigators revealed that ETV7 was abnormally overexpressed in a large proportion of cases in several types of cancer.
The team found ETV7 overexpression, for instance, in acute myeloid leukemia, acute lymphoblastic leukemia, "pediatric solid tumors," a type of pediatric brain tumor called medulloblastoma, and liver cancer.
Following this, they carried out cell culture tests and found that ETV7 caused mTOR to become overactive, and that this accelerated cell growth.
The scientists were mystified, however, by the fact that ETV7 did not seem to be doing this as part of the protein complexes mTORC1 or mTORC2.
Eventually, after another set of experiments, they found that ETV7 was orchestrating the assembly of a distinct mTOR protein complex to which they assigned the name mTORC3.
Removing rapamycin resistance
These experiments confirmed that neither mTORC1 nor mTORC2 contained ETV7 and showed that mTORC3 was completely resistant to rapamycin.
The scientists then demonstrated that deleting ETV7 in tumor cells that were resistant to rapamycin made them vulnerable to the drug.
A final set of tests in mice genetically engineered to develop tumors in their muscles showed that mTORC3 production made the tumors more aggressive and sped up their growth.
The researchers now plan to find drugs that block mTORC3 by targeting ETV7. They suggest that combining such a drug with those that target mTORC1 and mTORC2 could make many cancers vulnerable to rapalogs that are otherwise resistant to them.
"We have developed solid data for the existence of mTORC3, and now, we are seeking to isolate and identify the components of the complex."
Gerard C. Grosveld