Drug Strategy Blocks a Leading Driver of Cancer
UCSF Researchers Solve Decades-Old Challenge of Targeting Mutant Form of Protein
By Jeffrey Norris | UCSF.edu | November 20, 2013
The protein in cells that most often drives the development of cancers has eluded scientists' efforts to block it for three decades – until now.
Using a new strategy, UC San Francisco researchers have succeeded in making small molecules that irreversibly target a mutant form of this protein, called ras, without binding to the normal form. This feature distinguishes the molecules from all other targeted drug treatments in cancer, according to the researchers.
When tested on human lung cancer cells grown in culture, the molecules efficiently killed the ras-driven cancer cells.
Ras is abnormal in about three out of 10 cancers. It is the most commonly activated protein in lung tumors, the leading cancer killer in the United States, as well as in colon cancers, the third leading cause of cancer death. Ras also is mutated in a vast majority of pancreatic cancers, which are almost always fatal and the fourth leading cause of cancer death.
The protein has long been viewed as an obvious target for drug treatment in cancer, but since the 1980s drug candidates developed by several companies to block ras function have failed in clinical trials.
The UCSF research group, led by Kevan Shokat, PhD, a Howard Hughes Medical Institute investigator and chair of the UCSF Department of Cellular and Molecular Pharmacology, designed small molecules that attach irreversibly to ras within a previously unknown, normally short-lived pocket that appears on the mutant protein as it changes shape.
Their work was published online Nov. 20 in the journal Nature.
Targeting an 'Undruggable' Protein
Many experienced pharmaceutical chemists had come to regard ras as undruggable, Shokat said. Among the failed strategies were conventional approaches aimed at designing small molecules to compete with the molecule called GTP, which naturally activates ras within the cell. GTP binds so tightly to ras that it is difficult for any drug to compete by binding instead and blocking activation.
Kevan Shokat, PhD
But given its importance and the fact that few new cancer targets have been identified recently, drug companies have begun giving ras research another chance.
In its normal form, ras plays a key role in driving cell growth. When it is mutated, and thus activated in an uncontrolled manner, it triggers a chain of events within a tumor cell that includes abnormal activation or inhibition of other genes that then promote cancer. Some of the proteins encoded by these downstream genes have been targeted by promising treatments now in clinical trials. But tumors with abnormal ras often do not respond well to these single therapies, pushing researchers to evaluate various combinations of drugs.
The latest achievement further justifies a renewed interest in ras in the cancer research community and pharmaceutical industry, according to Frank McCormick, PhD, FRS, an expert on cancer biochemistry. McCormick is also the founder of Onyx Pharmaceuticals, director of the Helen Diller Family Comprehensive Cancer Center at UCSF, and now a leader of a new, $10-million-per-year initiative launched this year by the National Cancer Institutes to target ras.
“Cancers driven by ras are the most difficult to treat and are excluded from other targeted therapies, as they fail to respond,” McCormick said. “Dr. Shokat and his team have taken a brilliantly innovative approach to this tough target, and, for the first time, have developed a strategy for targeting a mutant form of ras with exquisite specificity.”