The initial response to a cancer therapy is often promising, with drugs successfully targeting and reducing the tumor burden. However, over a period of months or years, the treatment that was once effective frequently begins to lose its power, a phenomenon known as acquired resistance. This therapeutic failure occurs because cancer cells are highly adaptable, and the drug itself imposes a powerful selective pressure on the tumor population. Much like an antibiotic selects for resistant bacteria, the cancer drug eliminates sensitive cells, leaving behind a small population of cells with pre-existing or newly developed defenses that can thrive and repopulate the tumor.
Genetic Mutation and Pathway Bypass
Cancer cells possess high rates of genetic instability, which constantly generates random changes in their DNA. When a targeted therapy is introduced, it acts by inhibiting a specific protein, or molecular target, that the cancer cell relies on for growth and survival. The drug acts as a filter, allowing only those cells that have found a way around the inhibition to survive and multiply.
One common way cells evade therapy is by altering the drug’s target through a point mutation. For example, some lung and blood cancers treated with targeted inhibitors develop a secondary mutation in the target protein, such as the EGFR T790M mutation in lung cancer or the ABL T315I mutation in chronic myeloid leukemia. These changes in the protein’s shape prevent the drug from binding effectively, rendering the original treatment useless. The cell remains dependent on the modified target, but the drug can no longer deliver its inhibitory signal.
Another strategy involves increasing the amount of the target protein through a process called gene amplification. The cell makes many copies of the gene that codes for the target protein, flooding the cellular environment with the drug’s target. Even if the drug is present at high concentrations, there are too many target proteins for the drug molecules to inhibit them all, allowing signaling to continue.
Cancer cells can also achieve drug resistance by engaging an alternative survival route, known as pathway bypass. If a drug successfully blocks one signaling pathway, the cancer cell may activate a parallel pathway to maintain its growth and survival signals. For instance, when a cell’s main signaling route is blocked, it might increase the activity of a completely different pathway, such as the PI3K/Akt/mTOR or MAPK pathways, to compensate for the loss of the original signal.
This bypass mechanism can involve the activation of a different receptor on the cell surface. Resistance to a MET inhibitor can occur when the cancer cell starts to overexpress a growth factor that activates the epidermal growth factor receptor (EGFR) pathway. By switching its primary driver, the cell makes the original drug target irrelevant, allowing the tumor to continue proliferating despite the therapy. This genetic and signaling plasticity allows the tumor to evolve rapidly under the selective pressure of the drug.
Mechanisms of Drug Expulsion
Beyond genetic alterations to the drug target, cancer cells possess physical and biochemical mechanisms to neutralize the therapeutic agent. The most significant of these is the increased expression of drug efflux pumps, which function as tiny vacuum cleaners embedded in the cell membrane. These protein pumps are a primary cause of multidrug resistance, where the cell becomes simultaneously resistant to multiple chemically unrelated drugs.
These efflux pumps belong to a family of proteins called ATP-binding cassette (ABC) transporters, including examples like P-glycoprotein (P-gp), also known as MDR1, BCRP, and MRP-1. The pumps use energy derived from ATP to eject drug molecules from the cell’s interior back into the extracellular space. This action dramatically reduces the concentration of the drug inside the cell to sub-lethal levels before it can reach its intracellular target, such as the nucleus or a specific signaling protein.
The cancer cell can also develop resistance by chemically inactivating the drug. This is achieved by increasing the production of drug-metabolizing enzymes, which are normally involved in detoxifying the body. These enzymes chemically modify the drug molecule, breaking it down or rendering it non-toxic and inactive. This process neutralizes the agent.
Some cancer cells develop the ability to sequester drugs into internal compartments, such as lysosomes. By trapping the drug molecules inside these cellular vesicles, the cell effectively removes them from the cytoplasm. This compartmentalization allows the cell to survive the drug’s presence without having to physically expel it.
Influence of the Tumor Microenvironment
The environment surrounding the tumor mass, known as the tumor microenvironment, is an active participant in developing drug resistance. This external influence creates physical and chemical barriers that prevent the drug from reaching the cancer cells in sufficient concentration.
Many solid tumors are characterized by regions of low oxygen, a condition called hypoxia. Hypoxia triggers a stress response in cancer cells, altering the cell’s metabolism. This promotes dormancy and makes the cells less susceptible to chemotherapy drugs that target rapidly dividing cells.
The physical structure of the tumor also acts as a barrier to drug delivery. Tumors often contain a high density of supportive cells, like fibroblasts, and a dense network of connective tissue known as the extracellular matrix or stroma. This fibrotic tissue creates a physical shield that limits the drug’s ability to penetrate the mass and reach the cancer cells.
Non-cancerous cells within the microenvironment, such as immune cells and cancer-associated fibroblasts, secrete growth factors and cytokines, which promotes cancer cell survival and resistance to cell death. The microenvironment also fosters an immunosuppressive state, recruiting immune cells that suppress the body’s anti-cancer immune response, creating a protected niche where the cancer cells can evade therapy.