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Cancer Drug Resistance: Implications in Cancer Therapy
By T. Chakraborty, Ph.D.
Cancer is the second most common cause of death in the human population right behind heart diseases. Approximately 10 million people die of cancer every year which in turn is a huge socioeconomic burden to society. The United States alone had 1.7 million people diagnosed with cancer with approximately 600,000 deaths in the year 2018 . Even with the improvement of drug target identification and precision medicine, the field of cancer therapy continues to face the hurdle of drug resistance. Cancer cells often acquire the ability to survive and grow in the host through the process of drug resistance, which ultimately leads to the ineffectiveness of cancer therapies.
What is Cancer Drug Resistance?
It is well documented that overdose of antibiotics can cause antibiotic resistance in bacteria by the natural selection of resistant strains. Similarly, rapidly dividing cells can develop mutations and resistance towards the drugs which result in the selection of cancer cells resistant to therapies. Before the advent of immunotherapies, chemotherapy or molecularly targeted therapies via inhibitors were the most preferred cancer treatments. However, cancer cells have developed ways to evade these interventions and develop resistance against drugs. Some of these resistances are intrinsic, meaning, the individual has pre-existing factors that make the cancer cells resistant to the drug while some are acquired as the treatment progresses .
Drug Resistance Mechanisms in Cancer
Of the various known mechanisms, drug efflux is one of the major ones through which cancer cells evade therapies. Many transmembrane efflux pumps have been linked to the development of resistance towards chemotherapy and targeted molecular therapies. The most notable of these is the ATP-binding cassette (ABC) class of transporters. With around 49 members in this family, this diverse class of proteins has been shown to pump out the drugs from cancer cells, making them resistant. Of the 49 members, the predominantly studied proteins are multi-drug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP). Though MDR1 inhibitors like zosuquidar and tariquidar initially showed promise in pre-clinical studies, the trials failed probably owing to the redundancy and diversity of these ABC transporters [3, 4, 5].
Certain drugs can penetrate the cells through passive diffusion or absorption of solute carrier proteins (SLC). Cancers have been found to reduce the expression of these SLC proteins or reduce their binding capacity, thereby decreasing intake . They can also evade targeted therapies by changing their expression levels, a phenomenon they achieve by mutating drug targets. For example, androgen receptors are upregulated in prostate cancer patients who are treated with androgen receptor antagonists, bicalutamide. Increased target expression, in this case, reduces the drug efficacy leading to drug resistance .
Modifications in drug metabolism is another established mechanism. Higher activity of cytochrome P450 enzyme has been observed to induce resistance against breast cancer drug docetaxel. Reducing the enzyme activity increases drug efficacy, demonstrating the importance of drug metabolism in cancer drug resistance development [6, 8].
DNA damaging agents
Chemotherapeutic agents act against the cancers by damaging their DNA. The usual response to that is either cell death or DNA repair. Cancer cells have been shown to develop chemotherapeutic resistance by upregulating DNA repair mechanisms and inhibiting cell death by upregulating anti-apoptotic pathways. Molecular therapies against key proteins of the DNA repair machinery is a proven approach to deal with such a challenge. A prime example is a poly (ADP–ribose) polymerase 1 (PARP1) inhibitor that is used to combat drug resistance in breast cancer .
Cancer Heterogeneity and Tumor Microenvironment
The tumor microenvironment, and heterogeneity, that refers to the cell to cell variation, also play a critical role in the development of drug resistance . Resistant cells get selected during cancer growth and propagation through genetic alterations and the genetic diversity of a malignant tumor. Additionally, the tumor microenvironment that comprises of immune cells, vasculature, etc. mediates the development of drug resistance by inhibiting tumor clearance and drug absorption. The influence of this microenvironment has been further underscored by the success of immunotherapies and immune checkpoint blockade proteins like TIGIT, and others .
Fighting against Cancer Drug Resistance
Drug resistance can be mitigated by limiting the heterogeneity and genetic diversity of the cancerous tissue, something that could be achieved through early detection. The development of methods to detect circulating DNA from tumor cells has largely aided this cause . AVENIO family of next-generation sequencing assays by Roche is one such method that can be used for the rapid identification of circulating DNA in early cancer patients .
Other methods include local therapy targeted to cancer cells, immunotherapy using the immune-checkpoint proteins as well as monitoring the response to drugs from time to time to understand drug efficacy. Orthogonal therapies targeting multiple pathways is also a strategy that holds much potential. Using high throughput methods like next-gen sequencing on patient-derived cancer cells can provide valuable inputs on the intrinsic and extrinsic drug resistance at the genetic level.
Nanomedicine has been promoted as the future of cancer therapy as it has various properties to circumvent drug resistance development. Many nanoparticles mediated delivery is dependent on passive delivery and has been shown to have enhanced retention than traditional therapies. The addition of polyethylene glycol to nanoparticles has been shown to increase circulation time leading to higher drug absorption . Most of the nanoparticles are still under investigation. Of the current FDA approved therapies, Johnson and Johnson’s Doxil (doxorubicin HCl) authorized for ovarian cancer, breast cancer, and multiple myeloma is of particular interest .
Understanding the molecular basis of cancer drug resistance will open up new avenues in cancer treatments. Combining various strategies, like understanding the physical nature of the tumor, the microenvironment, genetic variations among others are gaining traction. Besides, studying the potential targets, early detection and targeted therapy will also help in reducing drug resistance. Furthermore, in the era of precision medicine, patient-derived organoids  could shed new light on the patient-specific drug resistance, the understanding of which will result in improved therapies.
Editor: Rajaneesh K. Gopinath, Ph.D.
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