Biological Mechanisms of Drug Resistance in Cancer Therapy

Combrzyński Jacek^*
*Correspondence: Combrzyński Jacek, Department of Pharmacy, University of Baltimore, Baltimore, USA, Email:

Keywords

Therapeutic • Cancer • Drug

Introduction

However, mutations in these target proteins can render the drugs ineffective. For example, mutations in the BCR-ABL gene in chronic myeloid leukemia can lead to resistance against tyrosine kinase inhibitors like imatinib. Similarly, mutations in the epidermal growth factor receptor in non-small cell lung cancer can result in resistance to EGFR inhibitors. These mutations often alter the binding site of the drug, reducing its efficacy and allowing cancer cells to continue to thrive. Another significant mechanism of drug resistance involves the increased efflux of drugs from cancer cells. This is often mediated by the overexpression of ATP-Binding Cassette (ABC) transporters, such as P-glycoprotein (P-gp) and Multidrug Resistance-Associated Proteins (MRPs). These transporters act as pumps, actively expelling drugs from the cells and thereby reducing their intracellular concentrations to sub-therapeutic levels. As a result, even if the drug enters the cancer cells, it is quickly pumped out, preventing it from exerting its cytotoxic effects. Overexpression of these transporters is a common feature in many types of cancer and is associated with resistance to a wide range of chemotherapeutic agents. Cancer cells can also develop drug resistance through the activation of alternative signaling pathways [1]. When a primary pathway targeted by a drug is inhibited, cancer cells may activate compensatory pathways to sustain their growth and survival. For instance, resistance to BRAF inhibitors in melanoma can occur through the activation of the MEK/ERK pathway [2].

Literature Review

Similarly, in breast cancer, resistance to HER2-targeted therapies can arise through the activation of the PI3K/AKT/mTOR pathway. These alternative pathways provide a bypass route for cancer cells to continue proliferating despite the presence of the drug, highlighting the complexity and redundancy of cellular signaling networks in cancer. The tumor microenvironment also plays a crucial role in drug resistance. The microenvironment consists of various noncancerous cells, such as fibroblasts, immune cells and endothelial cells, as well as extracellular matrix components. These elements can influence cancer cell behavior and drug response through direct cell-cell interactions and the secretion of various cytokines and growth factors [3]. For example, Cancer- Associated Fibroblasts (CAFs) can secrete Hepatocyte Growth Factor (HGF), which activates the MET receptor on cancer cells and promotes resistance to EGFR inhibitors. Additionally, the hypoxic conditions often found in tumors can induce the expression of hypoxia-inducible factors (HIFs), which can lead to resistance to radiotherapy and certain chemotherapeutic agents.

Discussion

Epigenetic modifications, such as DNA methylation and histone modifications, also contribute to drug resistance in cancer. These modifications can alter gene expression patterns without changing the underlying DNA sequence. In some cases, drug resistance can be mediated by the silencing of genes that are critical for drug sensitivity. For example, the methylation of the MLH1 gene promoter in colorectal cancer leads to the loss of mismatch repair activity and resistance to certain chemotherapeutic agents [4]. Epigenetic changes can also activate the expression of genes that confer drug resistance, such as those encoding drug efflux transporters or anti-apoptotic proteins. Another mechanism of drug resistance is the enhanced DNA repair capacity of cancer cells. Many chemotherapeutic agents and radiation therapies work by inducing DNA damage in cancer cells, leading to cell death. However, cancer cells can develop resistance by upregulating DNA repair pathways, allowing them to efficiently repair the damage and survive the treatment. For example, the overexpression of the excision repair cross-complementation group 1 protein is associated with resistance to platinum-based chemotherapy in various cancers. Similarly, the increased activity of poly polymerase can confer resistance to PARP inhibitors in BRCA-mutated cancers. Cancer Stem Cells (CSCs) also contribute to drug resistance. CSCs are a subpopulation of cancer cells with the ability to self-renew and differentiate into various cell types within the tumor [5]. These cells are often more resistant to conventional therapies compared to the bulk of the tumor cells. This resistance is partly due to the high expression of drug efflux transporters, enhanced DNA repair mechanisms and an increased ability to remain in a quiescent state. As a result, even if the majority of the tumor is eradicated by treatment, CSCs can survive and lead to tumor recurrence and metastasis.

Finally, autophagy, a cellular process involved in the degradation and recycling of cellular components, has been implicated in drug resistance. Autophagy can provide a survival advantage to cancer cells under stress conditions, such as those induced by chemotherapy or targeted therapies [6]. By breaking down damaged organelles and proteins, autophagy helps to maintain cellular homeostasis and energy production, allowing cancer cells to withstand the cytotoxic effects of the treatment. In some cases, the inhibition of autophagy has been shown to sensitize cancer cells to therapy, suggesting that targeting autophagy could be a potential strategy to overcome drug resistance.

Conclusion

Drug resistance in cancer therapy is a multifaceted problem involving a variety of biological mechanisms. These mechanisms include alterations in drug targets, increased drug efflux, activation of alternative signaling pathways, influences from the tumor microenvironment, epigenetic modifications, enhanced DNA repair, the presence of cancer stem cells and the role of autophagy. Understanding these mechanisms is essential for developing strategies to overcome resistance and improve the efficacy of cancer treatments. Ongoing research in this area holds the promise of identifying new therapeutic targets and approaches that can outsmart the adaptive capabilities of cancer cells and lead to more durable responses in patients.

Acknowledgement

None.

Conflict of Interest

None.

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