Drug Resistance of a Cell
Drug resistance can be categorized as intrinsic or acquired resistance based on the time when it is developed. Intrinsic resistance exists before drug treatment while the acquired resistance is induced after therapy, each occurring in about 50% of cancer patients with drug resistance.
Intrinsic resistance is usually defined as the innate resistance that exists before the patient is administered with (exposed to) drugs, which usually causes reduced efficacy of the drug treatment. Intrinsic resistance can be caused by: (1) pre-existing (inherent) genetic mutations in a majority of tumors that result in decreased responsiveness of cancer cells, such as triple negative breast cancer cells, to both chemo and target drugs; (2) heterogeneity of tumors in which pre-existed insensitive subpopulations, including cancer stem cells, will be selected upon drug treatment thus leading to relapse in later stages of therapeutic treatment; (3) activation of intrinsic pathways used as defense against environmental toxins (such as anticancer drugs).
Intrinsic drug resistance may exist in cancer cells prior to therapies due to the presence of genetic mutation(s) of genes involved in cancer cell growth and/or apoptosis.
Acquired resistance can be identified by gradual reduction of anticancer efficacy of a drug after the drug treatment. Acquired resistance can be a result of: (1) activation of second proto-oncogene that becomes the newly emerged driver gene; (2) mutations or altered expression levels of the drug targets; (3) changes in tumor microenvironment (TME) after treatment.
Shrunk tumors can acquire resistance and regrow due to new mutations. In one study, genomic profiles before and after relapse of eight acute myeloid leukemia patients were analyzed using whole-genome sequencing. The comparison of mutations between primary and relapse tumors revealed novel gene mutations. In addition, the results showed increased transversion mutations in relapsed tumors, suggesting that cytotoxic chemotherapeutic drugs caused DNA damage in cancer cells and might increase probability of the emergence of new mutations.
Cancer cells can acquire resistance to targeted drugs when the genes encoding target proteins develop new mutations or change expression levels.
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