Targeted therapy can indeed stop working over time, a phenomenon known as drug resistance. This resistance arises because cancer cells adapt and find ways to evade the effects of the drugs designed to kill or inhibit them. Although targeted therapies are initially effective by precisely attacking specific molecules or pathways critical to cancer growth, the cancer often evolves, rendering these treatments less effective or even ineffective.
One of the main reasons targeted therapy stops working is due to **genetic mutations** in the cancer cells. These mutations can occur in the very molecules that the drugs target, altering their structure so the drug can no longer bind effectively. For example, in lung cancer treated with ALK inhibitors, mutations in the ALK gene’s kinase domain can change the shape of the protein, preventing the drug from attaching and blocking its activity. Some mutations increase the protein’s activity or its ability to bind ATP (the molecule that fuels its function), which diminishes the drug’s inhibitory effect. These mutations are often called “gatekeeper mutations” because they block the drug’s access to its target site.
Besides mutations directly in the target protein, cancer cells can develop **alternative pathways** to survive. If the main pathway blocked by the drug is shut down, the cancer might activate a different signaling route that achieves the same goal of promoting growth and survival. This bypass mechanism means that even though the drug is working on its intended target, the cancer cells find a detour to keep growing.
Another mechanism involves changes in the **tumor microenvironment**, which includes surrounding cells, blood vessels, immune cells, and signaling molecules. The microenvironment can protect cancer cells from drugs by providing survival signals or by physically blocking drug access. For instance, immune cells or fibroblasts in the tumor area might secrete factors that help cancer cells resist therapy.
**Epigenetic changes**—which are modifications that affect gene expression without altering the DNA sequence—can also contribute to resistance. These changes can turn on or off genes that help cancer cells survive drug treatment, repair damage, or avoid cell death.
Sometimes, cancer cells undergo a process called **small cell transformation**, where they change their characteristics to a more aggressive form that is less sensitive to the original targeted therapy. This transformation can make the cancer behave differently and respond poorly to the drugs that once worked.
Resistance can be **primary** (present before treatment starts) or **acquired** (developing after initial response). Primary resistance means the cancer never responds well to the targeted therapy, often due to pre-existing mutations or alternative pathways. Acquired resistance develops after a period of effectiveness, as cancer cells evolve under the selective pressure of the drug.
Because of these resistance mechanisms, treatment strategies often need to adapt. This can include switching to **next-generation inhibitors** designed to overcome specific resistance mutations, combining targeted therapy with chemotherapy or immunotherapy, or using drugs that target multiple pathways simultaneously. Researchers are also exploring ways to modify the tumor microenvironment or reverse epigenetic changes to restore drug sensitivity.
In practice, managing resistance requires ongoing monitoring of the cancer’s genetic and molecular profile through biopsies or blood tests. This helps doctors identify new mutations or changes and tailor treatment accordingly. Despite the challenges, understanding how and why targeted therapies stop working is crucial for developing better treatments and improving patient outcomes.
