NEW YORK – Researchers from the Icahn School of Medicine at Mount Sinai have developed a heterobifunctional small molecule that degrades AKT, a gene in the PI3K–PTEN–AKT–mTOR pathway that is commonly mutated in cancer cells.
The Mount Sinai researchers published a preclinical cell line study of the AKT degrader, dubbed MS21, in Cancer Discovery last week. Now, they are hoping to ink partnerships with pharmaceutical companies to continue advancing the drug, said senior author Ramon Parsons, director of the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai.
According to Parsons, his team has begun talks with one large pharma company and three smaller drugmakers but would not disclose their names because the discussions are early and ongoing. However, Parsons noted that so far drug developers his team has engaged with are "intrigued" by this new drug.
The study that led to MS21 was spurred by previous attempts by the research community to make PI3K or AKT inhibitors. The early attempts at drugs targeting this pathway were too toxic, Parsons noted, but in May 2019, the first PI3K-targeted drug, alpelisib (Novartis' Piqray), was approved in the US for previously treated, HER2-negative, advanced, or metastatic breast cancer patients with PIK3CA mutations. That approval showed researchers that it was possible to advance a tolerable drug targeting this pathway.
Two pharma companies are already pursuing development of an AKT inhibitor: AstraZeneca's AZD5363 and Genentech's ipatasertib. AstraZeneca has begun early-stage trials of AZD5363 in tumors with AKT mutations and Genentech has an ongoing Phase III study of ipatasertib in breast cancer and a Phase I study in prostate cancer.
In the Cancer Discovery study, the Mount Sinai researchers compared MS21 to AstraZeneca's AZD5363 across 38 tumor cell lines. They found that MS21 inhibited more cell proliferation activity than AZD5363 in PTEN mutant cell lines. They also explored how MS21 compared to AZD5363 in mouse models and found MS21 resulted in more than 90 percent tumor growth inhibition versus placebo while AZD5363 resulted in 75 percent inhibition compared to placebo at the same dose over 21 days.
Only the glioblastoma cell line did not respond to MS21 treatment, Parsons said, but other major tumor cell types did, including breast, pancreatic, prostate, and ovarian cancer cells.
The researchers attributed MS21's better performance to its ability to lower the level of the AKT-related protein Aurora kinase B, or AURKB, in cells. They noted that AURKB was a substrate for AKT and was essential for cell proliferation.
"AURKB is cell essential, meaning if you don't have it, the cell can't proliferate and it dies when it tries to divide," Parsons explained. "That's a good thing for a cancer treatment."
Researchers determined that while other drugs targeting PI3K and ATK also lowered AURKB, MS21 appeared to lower AURKB levels the most. "That means that we may have a biomarker in the future to measure in the cells and see if they're going to respond or not," Parsons said.
The researchers also found that cell lines that harbored KRAS or BRAF mutations seemed to be resistant to treatment with MS21. These cell lines also had lower levels of AKT phosphorylation, which is the process that activates AKT. Without AKT phosphorylation in the KRAS- or BRAF-mutated cell lines, MS21 could not effectively degrade AKT and the AURKB protein.
They tested whether adding the MEK inhibitor trametinib (Novartis' Mekinist) to MS21 could overcome resistance due to KRAS and BRAF mutations because both genes signal through the MEK and ERK pathway. The researchers tested this combination in six tumor cell lines that had become resistant to MS21 and had no co-occurring mutations in the PI3K/PTEN pathway.
Two pancreatic cancer cell lines with a KRAS G12D mutation were sensitive to the combination, suggesting it "could improve the growth-inhibiting effect of single-agent trametinib in some type of cancer cells that carry KRAS mutations," they wrote. However, only the KRAS G12D cell lines appeared to respond to the combination treatment. And according to Parsons, his team is unlikely to pursue further study of this combination due to toxicity concerns.
Because of that, the researchers will continue to focus on tumors with PI3K/PTEN mutations. In an analysis of more than 46,000 tumor samples from the cBioPortal for Cancer Genomics database, they found that around 19 percent of patients only had mutations in the PI3K/PTEN pathway, including in PTEN, PIK3CA, AKT1, ERBB2, and PIK3R1. That represents a large treatment opportunity using an AKT degrader such as MS21.
Going forward, Parsons and his team will conduct additional preclinical studies of MS21 and continue discussion with pharma partners about its clinical prospects. Next, he hopes to explore different methods of delivery for MS21 beyond a daily injection. The research team will also evaluate toxicity, specifically the drug's effect on blood glucose, which increased with MS21 treatment and the other AKT inhibitors.
Parsons compared this study on MS21 and ATK degradation to the research on RAS inhibitors. Many in the research community had given up on KRAS as "undruggable" for many years before an agent that finally worked came along, Amgen's sotorasib (Lumakras), targeting the KRAS G12C mutation. The US Food and Drug Administration approved sotorasib earlier this year.
"Why I'm so passionate about this is because it's a very common pathway where we don't have a good solution and people have been working on it a long time. Many people are frustrated with that," Parsons said. "I have every expectation that with the right molecule, we'll be able to figure out a way to precisely target tumor cells [in the PI3K/PTEN pathway] with a good therapeutic window."