UCSF-led study offers insight into cancer development, resistance to therapy: finding focuses on Ras

UCSF-led scientists have determined that under certain conditions the Ras
oncogene, a key culprit in many cancers, suppresses the function of the p53
tumor-suppressor gene, offering an important insight into the development of
some cancers, and an explanation for why some cancers are resistant to
radiation therapy.

The finding is published in the current issue of Cell.

The Ras gene is part of a molecular pathway that transmits messages for cell
growth—an essential component of cell function—from the surface of the
cell into the cell’s nucleus. But when mutated, as it is in a third of cancers,
Ras functions like a gas pedal jammed to the floor, driving a cell into growth
and replication overdrive. If coupled with enough other mutations causing
destabilization of the cell’s growth controls, the Ras oncogene can contribute
to the development of cancer.

While Ras’s direct role in many cancers has been known, the new finding
suggests that, by regulating the p53 tumor-suppressor gene, Ras may play an
indirect role in many more, says the co-lead author of the study, Stefan Ries,
PhD, a postdoctoral fellow in the laboratory of senior author Frank McCormick,
PhD, director of the UCSF Comprehensive Cancer Center.

“Ras’s suppression of p53 could play an important role in inactivating the
tumor suppressor during the early stages of some tumor development. This may be
particularly true in colon cancers,” says Ries.

The p53 tumor-suppressor gene is one of several genes that serve as a protector
of a cell’s DNA. If DNA has been damaged, as can occur during DNA replication
and cell division or as a result of an environmental injury, the gene receives
a signal that it should halt the cell’s cycle of growth. If the cell repairs
itself, p53 releases its brake; but if the damage remains, p53 induces cell
death, which prevents the cell from continued growth and, ultimately, the
dividing into daughter cells containing its damaged DNA. Mutations are a form
of DNA damage, and it is the accumulation of mutations in certain critical
genes that nudge a cell into the uncontrolled growth that is the hallmark of
cancer.

The Ras oncogene’s ability to suppress p53 could explain, says co-lead author
Carola Biederer, PhD, a postdoctoral fellow in McCormick’s lab, why some
cancers are resistant to radiation therapy. Irradiation damages a cancer cell’s
DNA, and the theory behind its use is that, in the face of DNA damage, p53 and
other protectors of DNA health would be induced, ultimately causing death of
the cancer cell.

The p53 gene is mutated in 60 percent of cancers, and its inability to function
is one of the key steps undermining a cell’s control of its growth. However, in
40 percent of cancers, p53 remains intact, and researchers have sought an
explanation for how cells can become cancerous when this key watch guard
appears to maintain function.

Now, in a cell culture study of mouse embryo fibroblasts, the researchers have
shown that the Ras oncogene, itself, can deactivate p53. It does so indirectly,
by inducing a protein known as Mdm2, which degrades p53. But this degradation
only occurs if a gene known as p19ARF, which normally inhibits Mdm2, is
mutated.

“The study indicates that in a subset of the 40 percent of cancers in which p53
remains intact, Ras is playing a role in suppressing the activity of p53,” says
senior author McCormick.

Notably, in colon cancers, mutations in the Ras oncogene occur quite early in
the progression towards colon cancer, while p53 is degraded quite late. “Given
the circumstances we’ve described, there could be large number of tumors in
which mutant Ras plays a role in keeping p53 turned down,” he says.

Phase I (toxicity) trials of drugs that inhibit Ras are under way. If they are
effective, the explanation may prove to be that they prevent Ras from turning
off p53. And this, in turn, could enable p53 to induce the death of the cancer
cell.

Two recent findings hinted that the Ras oncogene might have a role in
regulating p53.  Two years ago, Israeli researchers showed that Mdm2 can be
activated not just by p53 but also by growth-promoting factors on the outside
of the cell that transmit their messages into the cell through the molecular
relay system of which Ras is one part. The team also participated in the
current study.

And last year a research group reported that Ras, in both the normal and
mutated form, can turn on p53, as a way of holding its own growth-promoting
activities in check. When the scientists mutated the Ras gene in cell culture,
the oncogene did not cause the cell to grow, because Ras had turned on p53. (Of
course, when p53 has been mutated by some factor, or disrupted by mutated
p19ARF, the Ras oncogene is able to function.)

The revelations illuminate the finely tuned system of checks and balances that
help maintain a cell’s healthy state—and which, if disrupted, contribute to
a cell’s spiral into cancer.

The researchers’ next step is to investigate whether the Ras oncogene
suppresses p53 in mouse models and in human tumors. They also plan to
investigate whether the Ras oncogene does induce resistance to radiation
therapy in cells in which p53 remains in tact, by examining human tumors that
have been resistant to radiation therapy.

Co-authors of the study were Douglas Woods, PhD, postdoctoral fellow in the
UCSF laboratory of Martin McMahon, PhD, of the UCSF Comprehensive Cancer
Center; Ohad Shifman, PhD student, at the Weizmann Institute of Science,
Rehovot, Israel; Senji ShiRasawa, MD, and Takehiko Sasazuki, MD, professors of
medicine at Kyushu University, Fukuoka, Japan; Martin McMahon, PhD, UCSF
associate professor of molecular pharmacology, of the UCSF Comprehensive Cancer
Center; and Moshe Oren, PhD, professor of biology at the Weizmann Institute of
Science.

The study was funded by the David A. Wood Foundation.

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