Chemotherapy, targeted therapies, immunotherapy, and hormone therapy have made it possible to control tumors that previously had very limited treatment options. However, even when a treatment works initially, it may eventually stop working without warning. As a result, the disease can progress, sometimes becoming even more aggressive than it was before treatment.
This phenomenon is known as treatment resistance, and it represents one of the greatest challenges in oncology. It does not necessarily mean that the treatment was chosen incorrectly or administered improperly. In many cases, it reflects a fundamental characteristic of cancer: its ability to evolve under pressure.
A review published in the DARU Journal of Pharmaceutical Sciences examines the cellular and molecular mechanisms that allow tumors to resist different anticancer drugs.
Resistance may be present from the beginning or develop during treatment
Intrinsic or primary resistance is present before the patient receives treatment. From the outset, the tumor may contain cells with characteristics that make them less sensitive to a particular drug. For this reason, some tumors respond poorly—or do not respond at all—to a therapy that would theoretically be expected to work.
Acquired resistance, by contrast, develops after an initial period of response. Treatment eliminates sensitive cells, but some cells manage to survive. These surviving cells may accumulate new mutations, change their gene expression, or activate alternative survival mechanisms. Over time, resistant cells multiply and begin to dominate the tumor, following the principle of “survival of the fittest.”
Treatment can therefore be understood as a selective pressure. It does not necessarily create every resistant characteristic, but it favors the survival of cells capable of withstanding therapy. The result is a form of accelerated evolution occurring within the body.
But if a tumor develops from the multiplication of only a few cells, shouldn’t all of its cells be similar?
A tumor is not a uniform population
One of the most important concepts for understanding resistance is tumor heterogeneity. Although a tumor may appear to be a single mass, it is actually composed of multiple cell populations with genetic, metabolic, and functional differences.
Some cells may grow rapidly, while others remain temporarily inactive. Some depend on a specific molecular pathway, whereas others use different mechanisms to survive. Even two regions within the same tumor may have distinct biological profiles.
This diversity may be genetic, phenotypic, spatial, or temporal. Spatial heterogeneity means that different areas of the tumor are not identical. Temporal heterogeneity means that the cancer continues to change as it evolves and responds to treatment. Consequently, a drug may destroy one cell population while leaving another resistant population intact.
This is also one reason why a single tissue biopsy does not always capture the full complexity of a cancer. The sample represents one region at one particular moment, while the tumor may continue to evolve afterward.
The therapeutic target can change
Targeted therapies are designed to block specific molecules that cancer cells need for growth and survival. However, cancer cells can alter the very target that the treatment is designed to attack.
A mutation may change the structure of a protein and prevent the drug from binding correctly. Cancer cells may also increase the amount of the therapeutic target, making the available drug concentration insufficient to block it completely.
A classic example occurs in some lung cancers with alterations in the epidermal growth factor receptor (EGFR). These tumors may initially respond to EGFR inhibitors but later develop secondary mutations that reduce the effectiveness of the drug. Similar mechanisms can affect therapies targeting HER2, BRAF, ALK, and other proteins.
Modifying the target, however, is not the only escape mechanism available to tumor cells. Cancer can also activate an alternative pathway. When one signaling pathway is blocked, another may take over part of its function. It is similar to closing a major highway while traffic finds a secondary route to reach the same destination.
Pathways such as PI3K/AKT/mTOR, MAPK/ERK, MET, and HER2 can function as alternative circuits that maintain cell proliferation and prevent cell death.
Cancer cells can expel or neutralize drugs
For a drug to be effective, it must reach the tumor, enter the cancer cell, remain there long enough, and achieve an adequate concentration. Resistant cells can interfere with any of these steps.
One of the best-known mechanisms is the overexpression of drug efflux pumps, which are proteins located in the cell membrane that transport substances out of the cell. P-glycoprotein, also known as P-gp or ABCB1, can reduce the intracellular concentration of anticancer drugs. This means that although the drug may be present in the bloodstream, its concentration inside the cancer cell may be too low to cause sufficient damage.
Drug metabolism also plays an important role. Some cancer cells increase the production of enzymes capable of inactivating drugs, while others reduce the enzymes needed to convert a prodrug into its active form. Genetic differences between patients, liver or kidney function, and interactions between medications can also affect the amount of active drug that ultimately reaches the tumor.
Cancer stem cells can remain hidden
Some tumors contain a small population of cells with stem cell-like characteristics. These cancer stem cells can self-renew, generate different tumor cell populations, and contribute to disease recurrence.
They often have more efficient DNA repair mechanisms, increased levels of anti-apoptotic proteins, and greater activity of drug efflux pumps. They can also enter a state of dormancy, meaning that they remain temporarily inactive.
This is important because many treatments primarily target cells that divide rapidly. A dormant cell may escape treatment and reactivate months or even years later. In addition, tumor cells that initially lack stem cell-like characteristics may acquire them through a process known as phenotypic plasticity.
For this reason, a significant reduction in tumor size does not always mean that every cell population capable of regenerating the tumor has been eliminated.
The tumor microenvironment can also provide protection
Cancer is not composed exclusively of malignant cells. Tumors are surrounded by blood vessels, immune cells, fibroblasts, extracellular matrix proteins, and signaling molecules. Together, these elements form what is known as the tumor microenvironment.
In many cases, this environment acts as a protective shelter. Cancer-associated fibroblasts can release factors that promote cell survival. Tumor-associated macrophages and regulatory T cells can create immunosuppressive conditions that weaken antitumor immune responses and reduce the effectiveness of some immunotherapies.
The extracellular matrix may also become denser and act as a physical barrier that prevents drugs from penetrating the tumor evenly. At the same time, tumor blood vessels are often abnormal and disorganized, resulting in an uneven distribution of treatment.
Another central component is hypoxia, or low oxygen availability. Hypoxia activates hypoxia-inducible factors such as HIF-1, which promote angiogenesis, modify cellular metabolism, increase repair mechanisms, and stimulate survival pathways. Hypoxia can reduce the effectiveness of radiation therapy, chemotherapy, certain targeted therapies, and even immunotherapy.
Figure 1. Major cellular and microenvironmental mechanisms that contribute to tumor heterogeneity and allow resistant cancer cell populations to survive treatment.
Resistance does not always require a new mutation
Cancer cells can also modify their behavior without changing the DNA sequence itself. This occurs through epigenetic mechanisms, which regulate which genes are switched on or off.
Some of the genes affected by these mechanisms may be involved in tumor destruction or may produce proteins that help control the disease. However, these protective genes may remain inactive because other molecules restrict their expression.
These changes are particularly important because they may appear rapidly and can sometimes be reversible. A cell may temporarily enter a drug-tolerant state and later acquire more stable alterations. Epigenetic regulation can increase drug efflux, alter metabolism, and block signals that would normally trigger cell death.
All of these mechanisms demonstrate the complexity of cancer and explain why, despite major advances in oncology, it is not always possible to speak of a universal “cure” or a treatment that is 100% effective. However, several strategies are being developed to address this challenge.
How can resistance be overcome?
Because resistance develops through multiple mechanisms, there is rarely a universal solution. One of the main strategies is to use combination therapies that block several mechanisms simultaneously. For example, one treatment may damage the DNA while another prevents the cell from repairing that damage. A targeted therapy may also be combined with chemotherapy or immunotherapy.
The objective is not simply to administer more drugs, but to select treatments with complementary mechanisms of action. These strategies must nevertheless be carefully balanced because combining therapies may also increase toxicity.
Precision medicine aims to identify mutations, active signaling pathways, and biomarkers that can help select the most appropriate treatment for each tumor. Genomic sequencing, transcriptomic analyses, liquid biopsies, and single-cell technologies can help detect changes associated with resistance and allow treatment to be adapted as the disease evolves.
Researchers are also investigating P-gp inhibitors, epigenetic modulators, and nanoparticle-based drug delivery systems. Another emerging strategy involves PROTACs, molecules designed to direct harmful or resistance-associated proteins toward the cell’s protein degradation machinery. Rather than temporarily blocking a protein, PROTACs are intended to eliminate it. However, clinical research remains at an early stage, and the benefits observed in preclinical models are not always reproduced in patients.
Treating a cancer that is constantly changing
Treatment resistance should not be understood as a single mechanism. Instead, it results from the evolution of a complex ecosystem. Mutations, tumor heterogeneity, cancer stem cells, epigenetic regulation, metabolism, and the tumor microenvironment can act simultaneously and reinforce one another.
The future of oncology will increasingly depend on viewing cancer as a dynamic process. This means studying not only what the tumor is like before treatment, but also how it changes during therapy and which cell populations survive.
Main reference:
Shaik, R., Malik, M. S., Basavaraju, S., Qurban, J., Al-Subhi, F. M. M., Badampudi, S., Peddapaka, J., Shaik, A., Abd-El-Aziz, A., Moussa, Z., & Ahmed, S. A. (2024). Cellular and molecular aspects of drug resistance in cancers. Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences, 33(1), 4. https://doi.org/10.1007/s40199-024-00545-8
Other references:
Assaraf, Y. G., Brozovic, A., Gonçalves, A. C., Jurkovicova, D., Linē, A., Machuqueiro, M., Saponara, S., Sarmento-Ribeiro, A. B., Xavier, C. P. R., & Vasconcelos, M. H. (2019). The multi-factorial nature of clinical multidrug resistance in cancer. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy, 46, 100645. https://doi.org/10.1016/j.drup.2019.100645
Rueff, J., & Rodrigues, A. S. (2016). Cancer Drug Resistance: A Brief Overview from a Genetic Viewpoint. Methods in molecular biology (Clifton, N.J.), 1395, 1–18. https://doi.org/10.1007/978-1-4939-3347-1_1
