A new study proposes a new therapeutic strategy for one of the deadliest types of cancer. By combining existing drugs, instead of directly targeting the central mutation that drives the disease, the researchers found an indirect way to weaken the tumor’s growth mechanism. The findings may affect additional types of cancer in the future.
Pancreatic cancer is considered one of the most difficult and lethal types of cancer to treat. One of its common forms is Pancreatic Ductal Adenocarcinoma – an aggressive tumor that is usually detected at an advanced stage and responds in a limited way to existing treatments.
Now, a new study presents an innovative therapeutic approach that may open new possibilities for dealing with the disease – using a combination of drugs already in medical use.
The central challenge: KRAS mutation
In the vast majority of pancreatic cancer cases, there is a mutation in the KRAS gene. The mutation causes the KRAS protein to remain constantly active and send signals that lead to uncontrolled division of cancer cells.
These signals pass through a biological pathway that includes, among others, the RAF-MEK-ERK signaling pathway, which activates mechanisms that promote tumor growth.
Although the KRAS gene is considered a central driver of pancreatic cancer, attempts to develop drugs that directly neutralize it have succeeded only partially. One reason is that a specific KRAS mutation – which can be targeted with drugs – is relatively rare in pancreatic cancer, and tumors tend to develop resistance to treatment.
Instead of trying to directly block KRAS, the researchers examined another mechanism in the cell’s regulatory system.
An important protein called RB1 acts as a kind of “brake” on the cell cycle and prevents uncontrolled division. When RB1 is active, it can inhibit KRAS activity and the signaling pathways that promote tumor growth.
However, in pancreatic cancer, RB1 activity is neutralized by another protein system called the Cyclin D1-CDK4/6-RB1 axis. This system shuts down RB1 and allows cancer cells to continue dividing.
Use of existing drugs
To restore RB1 activity, the researchers used drugs from the CDK4/6 inhibitors group – drugs already used in breast cancer treatment.
These drugs prevent the inactivation of RB1, thereby allowing it to resume its function as a tumor suppressor protein.
At first, it became clear that the drugs succeed in stopping cancer cell division and cause them to enter a special biological state called cellular senescence – a state in which the cell stops dividing but does not die.
Although the treatment succeeded in stopping tumor growth, it did not cause sufficient death of cancer cells. The researchers discovered that the cells are able to reactivate survival mechanisms.
It turned out that following the treatment, an additional signaling pathway is activated involving a receptor called EGFR. This pathway reactivates growth signals in the cells and helps them survive.
To overcome this survival mechanism, the researchers combined CDK4/6 drugs with drugs that block EGFR, including:• Gefitinib• Cetuximab
The combination of drugs succeeded in causing cancer cell death in various experimental models – including mouse models and human tumors implanted in experiments.
A new principle in treatment: Senolysis
The study also revealed another important therapeutic mechanism called senolysis – the selective elimination of cells that have entered a state of cellular senescence.
In the first stage, the drugs cause cancer cells to stop dividing and enter senescence. Afterward, EGFR pathway blockade causes the death of those cells.
The researchers emphasize that the treatment sequence is especially important: First, the drugs that induce cellular senescence must be given, and only afterward the drugs that eliminate the cells.
One concern in such treatment approaches is damage to healthy cells that enter senescence. To examine this, the researchers used advanced mouse models that allow tracking of senescent cells in the body.
The results were encouraging: No signs of cellular senescence were found in healthy tissues following the treatment, indicating the potential for a safe therapeutic window.
Implications beyond pancreatic cancer
The researchers note that the new approach may also be relevant to other types of cancer in which similar mechanisms exist involving interactions between oncogenic genes and tumor suppressor proteins.
Another advantage is the fact that the treatment is based on drugs already approved for medical use, which may accelerate the transition to clinical trials in humans.
Pancreatic cancer is currently considered one of the deadliest types of cancer, with extremely low survival rates. Therefore, any breakthrough in understanding the biological mechanisms of the disease may be significant.
The new study demonstrates how a deep understanding of molecular interactions within the cell can lead to new therapeutic strategies – even when the central target, such as KRAS, has long been considered undruggable.
If these findings are confirmed in clinical studies, it may eventually be possible to develop a more effective treatment for one of the most difficult cancers to cure.
Source:
www.jpost.com
