As many as half of all human cancers involve a defect in one cellular growth pathway. Most attempts to build drugs against it have failed, and some researchers started calling it “undruggable.”
In August 2018, a team at UC San Francisco and Redwood City-based Revolution Medicines reported a different route in Nature Cell Biology. Instead of attacking individual broken proteins, they tried to cut the whole RAS/MAPK pathway off from the growth signals that feed it.
Think of it like a Rube Goldberg machine. A growth signal from outside the cell lands on a receptor on the surface. That switches on the protein RAS, RAS recruits RAF, RAF activates MEK, and MEK stimulates MAPK, which sends growth instructions to the nucleus. Proteins such as the tumor suppressor NF1 keep the volume in a healthy range.
Turning down the volume
Earlier thinking held that cancer mutations always jam a protein in the “on” position. Newer work showed that some mutations only make the protein oversensitive to normal signals, turning up the volume on the whole pathway. Trever Bivona, the UCSF oncologist who led the study, reasoned that in those cancers, blocking the signal at its source could stop growth.
The compound they tested, RMC-4550, was discovered at Revolution Medicines and targets an enzyme called SHP2. SHP2 helps surface receptors activate RAS, and the compound decouples the pathway from outside growth signals.
The team ran it against several dozen cancer cell lines with mutations thought to depend on upstream signals, including class 3 BRAF mutations, a subset of KRAS mutations and loss of NF1. It slowed growth in multiple types of lung, melanoma, colorectal and pancreatic cancer cells, and sometimes killed the cells outright.
Tumor samples from patients grown in mice gave similar results. In models of five different non-small-cell lung cancers, RMC-4550 blocked tumor growth or shrank the tumors, with minimal side effects in the animals. “This was very exciting to me because it meant that the compound was not just arresting cell growth but actually killing cancer cells,” Bivona said.
Still preclinical
It was a preclinical study, and the results were waiting on human trials. Revolution Medicines planned to start those later that year with a different SHP2 inhibitor, RMC-4630, designed to suit patients.
Bivona expected the reach to be wide. “Almost every major oncogene I can think of coopts this pathway in one way or another,” he said, “and many of these cancers currently have no effective targeted therapies or eventually develop resistance to available targeted therapies.”
Bivona is on the Revolution Medicines Scientific Advisory Board and has received research grants from the company, and its employees were among the study’s authors.
