Chemoresistance occurs when cancer cells, once vulnerable to chemotherapy, adapt to survive and grow despite treatment. This cellular evolution is a significant challenge in cancer care. When chemotherapy drugs are introduced, they eliminate much of the tumor. However, some cancer cells may possess or develop traits that allow them to withstand the treatment, multiply, and cause a recurrence that no longer responds to the original drugs. This phenomenon is a primary reason why initial positive responses to treatment can be followed by a relapse.
How Chemoresistance Develops
Chemoresistance can be present from the outset, known as intrinsic resistance, or it can be acquired after exposure to chemotherapy. Acquired resistance is a common scenario where a tumor that was once shrinking begins to grow again because its cells have evolved to combat the medication. This adaptation can occur through several biological mechanisms.
One mechanism involves pumps on the cancer cell’s surface, such as P-glycoprotein. These structures actively force chemotherapy drugs out of the cell before they can cause damage, a process called drug efflux. This lowers the drug’s concentration inside the cell to ineffective levels. Cancer cells can amplify this ability by producing many copies of the genes responsible for these pumps.
Another way cancer cells develop resistance is by altering the drug’s target. Many chemotherapy drugs act like a key fitting a specific lock, such as a protein or DNA segment, to trigger cell death. Through genetic mutations, cancer cells can change the shape of this “lock,” preventing the drug from binding and working.
Cancer cells can also neutralize chemotherapy drugs directly by producing enzymes that break them down. Since many chemotherapy agents damage DNA, some cells counter this by enhancing their DNA repair systems. These repair mechanisms can fix drug-induced damage so quickly that the cell survives and divides, passing on its resistance.
Factors Influencing Chemoresistance
The tumor microenvironment (TME), the area surrounding the tumor, also heavily influences chemoresistance. This “neighborhood” consists of non-cancerous cells like immune cells, fibroblasts, and blood vessels, all embedded in an extracellular matrix. These components can shield cancer cells from chemotherapy and send survival signals that promote resistance.
A single tumor contains a diverse population of cancer cells, a concept called tumor heterogeneity. Some cells may already possess resistant traits before treatment begins. When chemotherapy is administered, it kills the susceptible cells, leaving the pre-existing resistant cells to thrive and repopulate the tumor. This process is similar to natural selection.
Cancer stem cells (CSCs) also play a part in chemoresistance. CSCs can self-renew and are often slow-growing or dormant, making them less susceptible to chemotherapies that target rapidly dividing cells. Even if most of a tumor is eliminated, these CSCs can survive and regenerate the tumor with increased resistance. The TME can also induce cancer cells to revert to a stem-like state, contributing to treatment failure.
Identifying Chemoresistance in Patients
Doctors identify chemoresistance primarily through clinical observation. If imaging scans like CT, PET, or MRI show a tumor is growing or has spread to other parts of the body during chemotherapy, it strongly indicates the treatment is no longer effective.
Blood tests measuring proteins called tumor markers can also signal resistance. Some cancers release these markers into the bloodstream, allowing their levels to be monitored. A consistent rise in a tumor marker after a period of decline suggests the cancer is growing again and the chemotherapy has lost effectiveness.
A new biopsy of the tumor can provide a more definitive understanding. This sample allows for molecular testing to uncover the specific resistance mechanisms. Genomic sequencing can identify new mutations in the drug’s target or amplifications of genes for drug efflux pumps. Identifying the reason for resistance helps guide the selection of a new, more effective treatment strategy.
Strategies to Overcome Chemoresistance
Once identified, several strategies can combat chemoresistance. One common approach is combination therapy, which involves administering multiple chemotherapy drugs that work through different mechanisms. This makes it harder for cancer cells to develop resistance to all drugs at once.
Targeted therapy is an effective strategy when molecular testing identifies a specific genetic mutation driving resistance. These drugs block specific pathways that cancer cells use to grow and survive. For instance, if resistance is caused by a new growth pathway, a targeted drug can shut it down.
Immunotherapy leverages the patient’s immune system to fight cancer. Treatments like immune checkpoint inhibitors can be effective against tumors that hide from the immune system, a mechanism sometimes linked to chemoresistance. These therapies unblock the immune response, allowing the body’s defenses to attack cancer cells.
Altering the chemotherapy dosage or schedule can sometimes help overcome resistance. Researchers are also developing new drugs to counteract specific resistance mechanisms, such as inhibitors that block drug efflux pumps. For patients with resistant cancers, clinical trials can provide access to innovative treatments and emerging strategies.