Drug Resistance Proteins

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Drug Resistance Proteins

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Drug Resistance Proteins Background

Drug Resistance in Cancer

Drug resistance is a major problem in cancer and the reason behind the inefficiency of chemotherapy to combat cancer. Cancer cells rely on several mechanisms to limit drug accumulation and action. These mechanisms include efflux pumps at the plasma membrane, compartmentalization of drugs, altered membrane lipids and increased repair of damaged DNA to avert apoptosis. The mechanisms used by cancer cells vary, depending on cell type and aberrations within the cell. Cancer cells have intrinsic resistance, which allow resistance to specific drugs. However, cancer cells tend to progress into acquired, multi-drug resistance, where specificity is no longer a limiting factor.

Cancer cells are capable of becoming resistant to therapy in several different ways, some of which act broadly to enable the cancer to become resistant to multiple drug types, whereas others are more specific and affect sensitivity to only one drug or class of drugs. Resistance can arise during the course of treatment (acquired resistance) or resistant cells can be present before the incitation of therapy (innate resistance). Regardless of how or when drug resistance arises, it ultimately results in a population of cells which are selected for and enriched during the course of treatment. Overtime, these cells may come to constitute the bulk of the tumor at which point therapy becomes ineffective and unless alternative therapies can be found the disease will progress.

Largely, drug resistance arises either through the over expression of pro-survival pathways or the down regulation of apoptotic pathways. Over expression or activating mutations in genes in pro-survival pathways such as the PI3K/Akt/mTor pathway can lead to cell survival. In the PI3K/Akt/mTor pathway for example, activating mutations in PI3KCA leads to hyperphosphorylation of phosphatidylinositol ultimately leading to the activation of Akt and mTor. Akt and mTor are then able to activate multiple anti-apoptotic molecules such as Bad, caspase 9 and various members of the forkhead transcription factor family. Alternatively, over expression of drug efflux pumps, specifically the ATP-binding cassette (ABC) transporter family can lead to resistance against a broad swath of anti-cancer compounds. By up regulating ABC transporter genes cells are capable of lowering intracellular drug concentration, thus reducing the effect the drug. Over expression of ABC transporter proteins can be inherent to specific tissues from which the cancer arises, however over expression can also be induced by chemotherapy exposure. For example, over expression of ABCB1 is associated with treatment failure in a wide range of cancers including kidney, colon, lung, as well as leukemias and lymphomas. Cancer stem cells show a higher drug resistance to therapy, expressing higher levels of drug eflux proteins.

Inactivating mutations in tumor suppressor genes can broadly affect drug resistance by disabling cell cycle checkpoints or inhibiting apoptosis. One of the most extensively studies examples is the tumor suppressor Tp53 which affects multiple survival pathway, including cell cycle regulation, senescence, DNA damage and repair. Disruption of Tp53-dependent apoptosis either through inactivating mutations in Tp53 itself or of components of the Tp53 pathway are essential for the development of lymphoproliferative diseases. As such the Tp53 status is an important prognostic indicator in lymphoid malignancies where it is associated with unfavorable outcome. Although the frequency of Tp53 mutations across all lymphoid malignancies is low, over 30% of BL samples possess mutated Tp53.

Besides these general mechanisms of drug resistance, cells are capable of undergoing alterations that are specific to individual drugs or families of drugs. Targeted therapy is more specific than traditional chemotherapy in that it is directed at specific genetic legions that are altered in cancer. The first clinically successful targeted therapy is the kinase imatinib which inhibits the Bcr-Abl fusion gene that is a hallmark of chronic myeloid leukemia (CML). Drug resistance to targeted therapies is often the result of either point mutations which prevent drug binding or activation of pathway components downstream of the target protein. In CML patients, drug resistance to imatinib is most often the result of the former with point mutations in the ATP binding domain of Bcr-Abl preventing imatinib binding.

B-cell lymphomas are highly heterogeneous malignancies and as such the mechanisms of drug resistance are varied. In B-cell lymphomas, mutations in the hematopoietic differentiation transcription factors ID3 and TCF3 (E2a) result in PI3K/Akt/mTOR pathway dependency. And mutations in this pathway lead to worse prognosis. As mentioned above mutations in p53 or p53 pathway components are essential to disease development and progression. The location of disruption of the pathway can have important clinical implications. Besides these intrinsic forms of resistance, B-cell lymphomas also experience acquired resistance. Up regulation of ABC family members or drug metabolism genes such as Adh1 frequently occur.

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