ADC Reviews

Research on AXL protein and drug resistance of targeted drugs


The excellent efficacy of targeted drugs and the inevitable problem of drug resistance have been in a state of ebb and flow. Researchers continue to explore solutions and try from various reasons and aspects, but the tumor cells are too cunning and have had little success.

The researchers found that when tumor cells respond to the attack of targeted drugs, they will initiate a stress response to induce more gene mutations to try to avoid the attack of targeted drugs, and a gene called AXL plays a key role.

So, if we start with AXL and block the AXL protein, can we overcome the drug resistance of targeted drugs?

SOS stress response in cancer cells

When we encounter a very urgent situation, the potential of the body is often unleashed. Scientists have found that bacteria, when faced with deadly threats, such as toxic chemicals, antibiotics, etc., also activate a dangerous but effective process called the SOS response. In this case, bacteria tend to make some more mistakes in gene duplication, so as to test how to survive the difficult situation. Most mutated bacteria die, but there are always some mutations that allow a very small number of bacteria to survive.

Similarly, when cancer cells resist tumor drugs, a similar SOS response occurs. When cancer cells are killed by a large number of drugs, gene replication in temporarily surviving cancer cells will produce more errors, and there will always be some cancer cells that have acquired drug resistance through gene mutation, thus surviving and proliferating , and ultimately achieve the purpose of resistance to drugs. Cancer cells develop the T790M mutation in the EGFR gene through this method.

In this trick played by cancer cells, there is a key central regulator AXL protein. If this protein is expressed in large quantities, drug resistance will soon appear. So now that the key to the problem has been found, the solution is naturally to find a way to block the AXL protein, so that cancer cells cannot initiate the SOS response, so the drug resistance problem of targeted drugs will not be solved? In fact, researchers have already started from this aspect. What is the effect?

To solve drug resistance, AXL protein antibody and Erbitux are indispensable

The researchers used an antibody against the AXL protein to block the AXL protein in mice, but it didn’t work. So researchers tried to combine it with targeted drugs. The commonly used targeted drug for EGFR gene mutation is osimertinib. The combination of AXL protein antibody and osimertinib still failed to solve the drug resistance problem.

The researchers continued to explore and added another anti-cancer drug Erbitux, which is an antibody-targeted drug against EGFR protein cetuximab. The result was a miracle: the tumor lesions did not develop drug resistance, and the tumor cells Permanently suppressed by targeted drugs.

However, if osimertinib, AXL protein antibody, and Erbitux are used in combination, the tumor lesions of the experimental animals are always zero, a straight line parallel to the X-axis, and there is no drug resistance problem, which solves the problem of targeted drugs. This is how drug-resistant combinations are created.


Solving the problem of drug resistance of targeted drugs has always been the direction of researchers, and the conclusions of this study undoubtedly allow us to see a glimmer of light. However, this study only focused on lung cancer. If it is other solid tumors, can the drug resistance problem be solved in the same way? The conclusions of the study still need to be confirmed by more clinical trials. At present, it is only an animal test. If the AXL protein antibody is to be used in humans, it needs to be humanized, which will take a long time.

In view of the excellent efficacy data in this study, it is believed that the researchers will conduct in-depth clinical research in this area in the future.