Mutations in the KRAS gene are the most aggressive type of solid tumor. They are responsible for one out of every four cancer deaths. A recent article published by Genentech Engineering News reported that UCSF researchers have modified an FDA-approve anticancer drug, cobimetinib, that halts the growth of tumors caused by KRAS gene mutations.
KRAS mutations cause cells to grow uncontrollably, evade death signals, and become resistant to several cancer treatments. Cells with the KRAS mutations acquire vast amounts of ferrous iron. However, certain drugs can block the signaling pathways and inhibit some KRAS-activated proteins while healthy cells remain unharmed.
About Cobimetinib and TRX-Cobimetinib
Dr. Adam Renslo, the co-senior author together with the UCSF team, modified a version of the MEK inhibitor, cobimetinib, called TRX-Cobimetinib. The result was a ferrous iron activatable drug conjugate (FeADC) that avoids healthy cells while only acting on iron-rich cells.
The new version, TRX-cobimetinib, has a molecular sensor that keeps the drug turned off unless it senses cancer cells containing ferrous iron.
This strategy could potentially be applied to wider use in cancers driven by mutations associated with the KRAS gene. Such mutations are especially common in colorectal cancer, pancreatic ductal adenocarcinoma, lung adenocarcinoma, and acute myeloid leukemia.
It is estimated that KRAS mutations drive one-quarter of cancer deaths through activation of cell signaling pathways and accommodating cell survival.
The Benefit and the Drawback
It is possible to block signaling pathways using drugs that block KRAS-activated proteins. The drawback, however, is that these drugs are toxic to tissues as well as healthy cells at the dose that is required to disrupt cancer cell signaling.
Dr. Eric Collisson of UCSF’s Hellen Diller Cancer Center is a senior author of a published report on the subject in JEM. The report notes that several FDA-approved inhibitors are toxic at the doses required to stamp out RAS/RAF/MAPK. (The MAPK/ERK pathway, a chain of the cell’s proteins, sends signals to DNA in the cell).
Dr. Collisson said that although MEK1/2 enzymes have clinical benefits, experience shows that toxicity sustainable doses are usually below that which the FDA has approved. Contrary to other drugs, the new drug does not affect retinal cells or human skin, yet it inhibits KRA-MEK pathways, blocks cell growth, and is well tolerated
Looking Forward
Dr. Renslo predicted that without the threat of toxicity in TRX-cobimetinib, it is conceivable that not just a single drug, but ten new drug combinations will be explored in the near future.
