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7 major drug resistance mechanisms of tumor drugs
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7 major drug resistance mechanisms of tumor drugs
Tumor cells are resistant to drugs through different mechanisms, some are primary drug resistance, some are acquired drug resistance, there are many mechanisms, mainly including the following seven aspects:
1. Increased drug efflux
One of the most direct ways for tumors to develop resistance to drug therapy is to block or restrict drug access to the site of action through physical mechanisms, one of which is through increased expression of ABC transporter family proteins such as MDR1, BCRPs, etc.
An effective drug must be able to pass through the cell membrane and must avoid being excreted by efflux transporters. Overexpression of efflux transporters is associated with resistance to many chemotherapeutic drugs, such as vinblastine, vincristine, doxorubicin, daunorubicin, and paclitaxel.
2. Decreased drug intake
The ability of tumors to reduce the uptake of drug molecules has also been suggested as a resistance mechanism. This mechanism is similar to how increased drug efflux reduces the concentration of drug molecules in the cellular environment, thereby limiting their efficacy against target tumors.
Drug molecules most susceptible to this resistance mechanism are chemotherapeutic drugs such as methotrexate, 5-fluorouracil, 8-azaguanine, and cisplatin, which have been shown to utilize transporters such as solute carriers (SLCs) to enter in the cell.
3. Drug inactivation
Many antitumor drugs have relatively complex mechanisms of action, and some require metabolic activation.
For example, cytarabine (ara-C) is a nucleoside-containing drug most commonly used in patients with acute myeloid leukemia.
Deoxycytidine kinase catalyzes the conversion of drugs to cytarabine monophosphate, which is subsequently phosphorylated to the active substance cytarabine triphosphate.
Mutation or downregulation of enzymes such as deoxycytidine kinase has been reported to induce drug resistance .
Metabolic inactivation of such nucleoside analogs can also be achieved through the actions of adenosine deaminase, cytidine deaminase, and purine nucleoside phosphorylase, among others.
Drug metabolism activities of the cytochrome P450 family are also involved in this resistance mechanism.
Irinotecan, an inhibitor of topoisomerase I, is used in colon cancer treatment, and the concentration of P450 can be induced or up-regulated during drug treatment, resulting in massive metabolism of the inhibitor and reduced drug exposure in patients.
Drug binding to glutathione (GSH) is also involved in this resistance mechanism. GSH is an antioxidant that helps protect cells from reactive oxygen species (ROS).
When platinum-containing anticancer drugs such as cisplatin and oxaliplatin bind to GSH, it makes them substrates for ABC transporters, thereby enhancing drug efflux.
These drugs may also be readily bound by the small cysteine-rich protein metallothionein (MT), thereby inactivating them.
4. Target mutation
Drug targets may acquire resistance to therapeutic molecules in a number of ways, of which target mutation is one of the most common mechanisms.
The Cancer Genome Atlas (TCGA) uses sequencing methods to identify mutations in thousands of tumors across 12 major cancer types.
Activating mutations in oncogenes such as EGFR, RAS, RAF, and PI3K are key drivers of a variety of cancers, and many tumor suppressor genes such as PTEN, Rb, and p16INK4a are mutated and inactivated, and these gene mutations can affect the properties and behavior of proteins. multiple influences.
4.1. Steric hindrance
Steric conflict, or interference with the ability of an inhibitor to interact with the binding site, is a common mechanism of amino acid mutation or aberration resistance. Amino acids may have different size, shape, charge and electrostatic properties that can directly alter the ability of the drug to interact with the target molecule.
One of the more common mutations affecting drug molecule binding is the substitution of small amino acids by large amino acids, resulting in steric conflicts and reduced binding affinity of the drug molecule.Alternatively, mutating polar amino acid side chains to hydrophobic amino acids or vice versa may disrupt polar interactions such as hydrogen bonds, etc.
Resistance mutations usually result in single base or amino acid substitutions. A well-recognized example is the T315I mutation of ABL when treating patients with chronic myeloid leukemia.
This residue is called the “gatekeeper” in protein kinases because it affects the size and nature of the binding group in the “selective” or “back” pocket. In this example, the “wild-type” residue is a small, hydrophilic threonine, which was replaced by the T315I mutation for a larger, more lipophilic isoleucine, leading to interactions with targeted drugs such as imatinib space conflict.
Thus, coding mutations in gating residues in protein kinases are among the most common sites of resistance, and this has also been observed in many other kinases such as EGFR, ALK, and ROS1.
4.2. Affinity changes
If the mechanism of action (MOA) of a drug molecule is achieved through competition with a cofactor (or substrate), then drug resistance will arise if the affinity of this cofactor or substrate to the target protein increases.
One of the most typical examples of this effect is the effect of the T790M gating mutation in EGFR on the activity of inhibitors such as gefitinib and erlotinib.
When this mutation was first discovered, it was thought that it most likely affects through steric hindrance, similar to T315L in BCR/ABL.
However, it was later found that the main effect of the T790M mutation was due to the increased affinity of the kinase for adenosine triphosphate ( ATP), making these drugs significantly less active in cellular experiments.
4.3. Conformational changes
In BCR/ABL, the L248V mutation leads to imatinib resistance through steric hindrance, while Y2 53C and E255K/V etc. disrupt the inactive conformation of the protein , resulting in inactive conformations bound by “type II” inhibitors Stable and resistant, this phenomenon often occurs in the “P-loop” mutation of the kinase.
5. Changes in signaling pathways
In some cases, cancer cells can achieve resistance to therapy by altering driver genes , which may involve reactivation of the targeted signaling pathway, or an alternative pathway that is activated to circumvent targeted inhibition.
For example, in the treatment of BRAF- mutated melanoma with RAF inhibitors , NRAS, MEK, and ERK mutations, BRAF amplification and alternative splicing, alternative regulation of MAP-3 kinase, etc., are likely to reactivate RAS–MAPK by reactivating RAS–MAPK. pathways to independently drive drug resistance.
6. Apoptosis defect
The ultimate goal of most cancer drugs is to trigger selective cell death in tumor cells, and disruption of apoptotic mechanisms may affect resistance to anticancer drugs, especially some chemoresistance that appear to be associated with defects in cell death mechanisms.
Recent studies have shown that the anti-apoptotic protein MCL-1 plays a key role in the adaptive resistance of tumor cells to a range of targeted therapies.
7. Phenotypic Conversion
Phenotypic switching (also known as “cellular plasticity”) is a change between multiple cell morphologies that can serve as a resistance mechanism independent of drug-targeted pathways.
This plasticity of tumor cells may lead to a phenotypic transition where the phenotypic state is no longer dependent on the drug-targeted pathway.
Recently, cellular plasticity has been found to be associated with resistance to targeted therapy in multiple cancer types, including melanoma, lung cancer, and basal cell carcinoma.
Transdifferentiation and epithelial-mesenchymal transition (EMT) are both examples of cellular plasticity that lead to drug resistance.
As an example of transdifferentiation, phenotypic transformation of EGFR-mutant lung adenocarcinoma (LUAD) to small cell lung cancer (SCLC) has been suggested as a clinical mechanism of EGFR inhibitor resistance.
A recent study showed that EGFR inhibitor-resistant LUADs and SCLCs share a common clonal origin and branched evolutionary trajectory.
The clonal differentiation of SCLC progenitors from LUAD cells occurred before drug treatment, and RB1 and TP53 were completely inactivated in the tumor at the early stage of LUAD.
Epithelial-mesenchymal transition (EMT) is a key mechanism of tissue remodeling during the morphogenesis of multicellular organisms. The causal relationship between EMT and tumor metastasis is not fully understood; however, the role of EMT in drug resistance has been repeatedly identified.
Understanding the mechanisms of phenotypic switching and the role in drug resistance at the molecular level may lead to new therapeutic strategies that in turn lead to deeper and longer-lasting cancer treatments.
7 major drug resistance mechanisms of tumor drugs
(source:internet, reference only)
Important Note: The information provided is for informational purposes only and should not be considered as medical advice.