One of the most commonly mutated pathways in human cancers involves the tumor-suppressor gene PTEN and the protein AKT, which regulates cell growth and proliferation and is overactive in many types of cancer. Biopharmaceutical companies have been developing and testing drugs to inhibit AKT for nearly two decades. But, to date, no therapies that block AKT have been approved for use in the clinic. In some cases, these investigational drugs appear to cause serious side effects. In other cases, the tumors acquire resistance and quickly recur.
Ramon Parsons, MD, PhD, Director of The Tisch Cancer Institute, who first identified the PTEN gene 20 years ago, and Jian Jin, PhD, Mount Sinai Professor in Therapeutics Discovery, are working on a new approach to target the PTEN/AKT pathway. The researchers have engineered a synthetic compound—a small molecule called MS21—that essentially hijacks the cellular machinery responsible for regulating quality control and degrading toxic proteins.
In their July 23, 2021, study in Cancer Discovery, the researchers showed that MS21 binds to AKT in much the same way as a drug designed to inhibit the protein, but also binds to a second protein, the E3 ligase. Bringing these proteins together in close proximity induces the degradation process and “seals AKT’s fate,” says Dr. Jin. “In order to work, a protein inhibitor must bind to AKT and be there all the time. When we degrade the protein, we get rid of it, and it’s gone.”
MS21 degrades AKT, rendering it incapable of acting on other proteins.
The study also found for the first time that degrading AKT significantly lowered the expression of another enzyme, Aurora kinase b (AURKB). AURKB is known to be overexpressed in many cancers but had not previously been identified as a component
in the PTEN/AKT pathway. Essentially, MS21 degrades or breaks down AKT, rendering it incapable of acting on other proteins, such as AURKB. Degrading AKT subsequently reduces the expression of AURKB, which, in turn, halts the growth and proliferation of tumor cells.
The researchers tested MS21 with human cancer-derived cell lines from multiple tumor types in vitro (in cell culture) and in vivo (in mice). Once they found the compound was not toxic, they proceeded to test its effectiveness, studying both sensitivity (a response) and resistance (lack of response). MS21 was highly effective in reducing tumor cell growth in PTEN pathway mutations unless they also contained BRAF and KRAS mutations—genes that are also commonly mutated in cancer—in which case it was not effective.
An analysis of more than 46,000 human cancer tumor specimens revealed that 19 percent had at least one PTEN/AKT gene mutation and no BRAF-KRAS mutations. “These results indicate that a large population of patients could potentially benefit from treatment using an AKT degrader such as MS21,” says Dr. Jin.
An analysis of more than 46,000 human cancer tumor specimens revealed that 19 percent had at least one PTEN/AKT gene mutation and no BRAF-KRAS mutations, indicating that many patients could potentially benefit from an AKT degrader such as MS21.
-Jian Jin, PhD
“We are optimistic about MS21’s safety and potential for efficacy in treating cancers with PTEN pathway mutations,” says Dr. Parsons. “PTEN is one of the top mutated genes in at least 21 different cancers and yet we have almost no effective PTEN drugs. We have a long process ahead of us, but the potential for impact is huge.”
The researchers say next steps will be producing sufficient quantities of MS21 for
testing in another preclinical animal model, gaining approval for MS21 as an investigational drug, and designing a research protocol for testing the compound’s safety in a human clinical trial. The team has patented the compound and is seeking potential industry partners as the research advances.
