Natural KRAS Inhibitors

The KRAS gene encodes a protein that plays a major role in controlling cell growth and cell death. As such, mutations in the KRAS gene can lead to unrestricted cell growth and cancer. Specific KRAS mutations have been found in pancreatic cancer patients and patients with other cancers. Therefore, inhibiting the proteins associated with mutated KRAS genes is a major goal of oncology drugs. However, natural substances that act in the same way as KRAS-inhibiting medications have recently been discovered as well, and their use for medical treatment of pancreatic diseases is currently being studied. 

Role of the KRAS Gene in Pancreatic Cysts

There are three major types of pancreatic cysts, all of which include more specific subtypes. The main categories include:

• Benign: Benign pancreatic cysts, also called pseudocysts, are non-cancerous. Benign cysts are caused by pancreatitis or trauma.
• Mucinous: Also known as mucinous cystic neoplasms, mucinous pancreatic cysts are not yet cancerous, but they have the potential to become cancerous. Mucinous cysts typically affect middle-aged women and are considered precancerous.
• Malignant: Malignant pancreatic cysts have already become cancerous and have the potential to spread to other areas of the body if left untreated.

The main way to differentiate between the various types of cysts is by analyzing the fluid within a cyst. Mucinous pancreatic cysts often contain KRAS gene mutations, which can lead them to become cancerous through uncontrolled cell growth. The most common KRAS mutation is the KRAS G12C mutation, caused by variation of a single nucleotide from the wild-type gene.

In its mutant form, the KRAS gene codes for a protein that interacts with calmodulin (CaM), a calcium-binding protein. Through this interaction, the KRAS-CaM complex initiates a biological pathway that leads to tumor growth. Disruption of this pathway without affecting wild-type KRAS proteins  is a major goal of oncology drugs. 

Kras-Inhibiting Drugs

There are two main KRAS-inhibiting drugs that have currently been developed for use against the mutant KRAS protein. These are:

• Sotorasib: Sotorasib, which has the brand name Lumakras, is a KRAS G12C inhibitor that was approved by the FDA in 2021. Sotorasib is a selective inhibitor, which means that it inactivates the mutant KRAS protein without impacting the function of wild-type KRAS proteins. It is being hailed as a major advancement in cancer therapy because selective KRAS inhibition was previously thought to be unachievable by medications. Although it can be used for gastrointestinal cancers such as pancreatic cancer, sotorasib is most effective against non-small cell lung cancer. 
• Adagrasib: Adagrasib has not yet been approved for use by the FDA, but it is currently in the approval process. Like sotorasib, it is a KRAS inhibitor, but it has been found to be more effective than sotorasib in patients with gastrointestinal cancers. In patients with pancreatic cancer, adagrasib has been found to have a 41% response rate. More catered to patients with pancreatic, colorectal, and esophageal cancer, adagrasib will become a competitor of sotorasib if it achieves FDA approval.

Natural KRAS Inhibitors

In addition to the new synthetic KRAS inhibitor drugs that are emerging, there are several natural compounds that have been found to inhibit mutant KRAS proteins, along with the mutant proteins of other RAS genes. These are:

• 5-O caffeoylquinic acid (5-CQA): Found in coffee beans, 5-CQA has a structure similar to synthetic drugs that inhibit RAS activity. It works by inhibiting interaction between RAS proteins and activator and effector molecules, and it has been shown to have anticarcinogenic activity in breast cancer cells. 
• Lupeol: Lupeol has been shown to be a specific KRAS inhibitor, selecting for and inactivating mutant KRAS proteins while leaving wild-type KRAS proteins active. It functions by inhibiting an enzyme that leads to the growth of cancer cell lines caused by  mutant KRAS genes. Lupeol is contained in white cabbage, green peppers, strawberries, olives, mangoes, and grapes. 
• Swinhopeptolides: Swinhopeptolides are isolated from a marine sponge. They inhibit the signaling pathway that starts with the interaction between the mutant RAS protein and one of its key protein kinases. 
• Prostratin: A natural compound found in the bark of a Samoan tree, prostratin specifically inhibits the interaction between mutant KRAS proteins and calmodulin. This interaction is vital to tumor growth, and prostratin suppresses cancer growth by hindering it. 

These compounds are all similar in structure and function to synthetic KRAS inhibitors, and they show promise for future use against various types of cancer, including pancreatic cancer. 

Summary

The KRAS gene plays a major role in controlling cell growth. The protein it encodes interacts with a variety of enzymes, activators, and effectors to begin important biochemical processes. When the KRAS gene is mutated, it results in a protein that leads to unchecked cell growth and various types of cancer. 

KRAS mutations can be detected within the fluid of pancreatic cysts. These mutations are typically found in mucinous, or precancerous, cysts. The mutant KRAS protein works with calmodulin to begin a process of unrestricted cell division that leads to pancreatic cancer. 

Two main synthetic drugs, sotorasib and adagrasib, have been made to selectively inhibit mutant KRAS proteins while allowing wild-type KRAS proteins to function normally. Sotorasib is approved by the FDA and is most effective against non-small cell lung cancer. Adagrasib is awaiting FDA approval and shows more promise against gastrointestinal cancers, including pancreatic cancer.

Various natural compounds, including 5-CQA, lupeol, swinhopeptolides, and prostratin, have similar properties to synthetic KRAS inhibitors. These compounds can potentially be used as anticarcinogenic agents in the future, but more research is needed regarding their mechanisms and characteristics before this can be possible.