- Why are vegetarians more likely to suffer from depression than meat eaters?
- Small wireless device implanted between skin and skull helps kill cancer cells
- Will the mRNA vaccine that can cure cancer come out near soon?
- Allogeneic T-cell therapy set for landmark first approval
- Boston University denies that the new COVID strain they made has 80% fatality rate
- A new generation of virus-free CAR-T cell therapy
Cancer Discovery: Targeted degradation of AKT can effectively treat a variety of cancers
Targeted degradation of AKT can effectively treat a variety of cancers. The serine/threonine kinase AKT is a key molecule in the PI3K-PTEN-AKT-mTOR signaling pathway. Mutations in the oncogenes PIK3CA and AKT1 and the tumor suppressor gene PTEN activate the AKT kinase and downstream mTOR kinase complex to initiate cancer development.
Genetic studies have shown that tumors caused by PTEN mutations are dependent on PI3K and AKT1. In the multi-gene engineering mouse model system, targeting the kinase on the PI3K-PTEN-AKT-mTOR signaling pathway can inhibit tumor growth caused by any of the above-mentioned cancer driver genes.
Translating these findings into effective cancer treatments is a top priority, because the PI3K-PTEN-AKT-mTOR signaling pathway may be the most common activation-driven pathway in human cancers. However, the growth of PIK3CA mutant tumors depends on PI3Ka. In the case of PTEN-driven mutations, people usually selectively inhibit PI3Ka, but this in turn activates other kinases and reduces the efficacy of selective inhibitors. Therefore, although PI3K inhibitors are useful for PIK3CA mutant cancers, the selective targeted therapy of PI3K inhibitors for PTEN mutant cancers is more challenging.
Recently, a research team from the Cancer Institute of Icahn Medical College of Mount Sinai published a research paper titled: AKT degradation selectively inhibits the growth of PI3K/PTEN pathway mutant cancers with wild type KRAS and BRAF by destabilizing Aurora kinase B in Cancer Discovery. .
The research team used tumor cell lines to identify a new type of AKT degradation product-MS21. In the mutant PI3K/PTEN pathway, AKT degradation can inhibit tumor cell growth more persistently than AKT kinase inhibition. Pan-cancer analysis found that 19% of cases had mutations in the PI3K/PTEN pathway, suggesting that AKT degrading agent treatment can benefit these cancer patients.
In order to develop an effective bifunctional hybrid AKT small molecule degradation agent, the research team evaluated the effects of three AKT inhibitors on the level of AKT protein, and determined that MS21, which recruits VHL E3 ligase, was used as the lead compound. Competitive binding analysis also showed MS21 is a high binding affinity AKT targeted degradation agent.
Next, the research team evaluated the effects of MS21 on tumor cell lines and determined how the AKT pathway regulates the Aurora Kinase B (AURKB) protein (a protein essential for cell division). They used MS21 to treat PTEN-mutated prostate cancer cell lines and PIK3CA-mutated HER2-positive breast cancer cell lines separately. The results showed that compared with the protein that affects AURKB, MS21 doubled the mRNA of AURKB, indicating that the consumption of AURKB protein increased. Further research found that AKT directly phosphorylated AURKB threonine 73, indicating the possibility of PI3K/AKT regulating AURKB at the protein level.
In most KRAS or BRAF mutant cells, MS21 cannot effectively degrade AKT. So the research team used MS21 combined with MEK inhibitors to evaluate their effects on MS21 drug-resistant cell lines. The results showed that MEK inhibition increased the phosphorylation of AKT and promoted the degradation of AKT by MS21. In addition, degradation resistance is related to low AKT phosphorylation, wild-type PI3K/PTEN status and KRAS/BRAF mutations.
Finally, by testing the ability of 38 different cell lines MS21 to inhibit cell growth, the research team found that MS21 inhibited the growth of 17 of 18 PI3K/PTEN pathway mutant cell lines without RAS pathway mutations. Importantly, MS21 has a better effect on inhibiting tumor cell lines with mutations in the PI3K/PTEN pathway than the currently routinely used AKT inhibitor AZD5363.
Overall, the study provides robust evidence to support the effect of MS21 in degrading AKT. It also reveals a new AKT substrate phosphorylated protein AURKB, which is a new type of clinical development for the treatment of patients with a wide range of oncogene mutations. AKT degradation agent has laid a solid foundation.
(source:internet, reference only)