Selective targeting of cancer cells: the conception and application of synthetic lethality

The development of anticancer treatments has remained an elusive goal until recently. However, an expanding cadre of targeted therapeutics in clinical use illustrates the enormous potential of thisapproach. Genetic alterations in cancer in humans may involve gene activation, amplification, or inactivation. These genetic features that are unique to the malignant cells can be exploited to develop treatments that are inherently tumor-specific. Synthetic lethality was first described by the American geneticist Calvin Bridges in the early 20th century. He noted that when crossing fruit flies (Drosophilamelanogaster), certain non-allelic genes were lethal only in combination even though the homozygous parents were perfectly viable. The term synthetic lethality was coined some 20 years later by his colleague Theodore Dobzhansky who observed the same phenomenon in Drosophila pseudoobscura. Synthetic lethality is a type of genetic interaction where the co-occurrence of two genetic events resultsin organismal or cellular death (Fig. 1 ). Although best known in the context of loss-of-function mutants, combinations of other types of perturbations can also result in synthetic lethality, including overexpression of genes, the action of a chemical compound or environmental change. Multifaceted, yet coordinated, DNA-damageresponse pathways, cell-cycle checkpoints, and alterations in transcriptional regulation attempt to maintain genomic integrity (Fig. 2). DNA-damage checkpoints are cell-cycle–integrated surveillance mechanisms that can attenuate propagation of damaged DNA, andcheckpoint activation is predominantly under the control of genes encoding the ATM (ataxia– telangiectasia mutated), ATR (ATM and Rad3–related), and DNA-dependent protein kinases. Double-strand DNA breaks can be highly deleterious to genomic integrity and may be associated with chromosomal translocation, cell death, and carcinogenesis.11 The classical nonhomologous end-joiningpathways and the alternative nonhomologous end-joining pathways are primarily responsible for repair of double-strand breaks at the G0, G1, and M phases(8, 9). In contrast, homologous recombinationuses homologous sequences elsewhere in the genome, preferably the sister chromatid, as the template to facilitate DNA repair during the S phase(10). The MRN complex (MRE11 [meiotic recombination11] RAD50–NBS1 [Nijmegen breakage syndrome protein 1]) localizes to the double-strand break, where it facilitates DNA processing, enhances ATR-dependent checkpoint signaling, and subsequentlyrecruits pivotal repair mediator molecules such as RPA and RAD51. ATM may also be recruited to sites of double-strand breaks by MRN; the MRN complex functions both upstream and downstream ofATM(11). In addition, BRCA1 protein has been shown to colocalize with RAD51. This colocalization contributes substantially to homologous- recombination competency. The aim of recent anticancerstrategies is to provide highly selective therapy. The treatment model for many anticancer approaches has been expanded, with movement away from dose-intense nontargeted cytotoxic agents to combination chemoimmunotherapy, new therapeutic combinations, and targeted agents. The application of synthetic lethality in developing new therapeutic strategies is in its infancy. Exploitation of the reliance of the cancer cell on specific pathways or conditions can enhance the therapeutic index between tumor and normal tissues. The development of unbiased, top-down, large-scale approaches with the use of screening libraries and genomic profiling has greatly accelerated knowledge in this field. These techniques have provided opportunities for finding of new targets and therapeutics, as well asfacilitation of individualized responsiveness prediction (e.g., BRCAness or PTEN loss). synthetic lethality also provides chances to follow targets that theoretically are not druggable and may perhaps permit reductions in the doses of conventional cytotoxic chemotherapy. In conclusion, the progress in understanding the potential of synthetic lethality for selective therapeutic targeting of cancer has not yet been matched by progress in its clinical application. Nevertheless, synthetic lethality is a promising rationale that is ready for clinical testing. Time will tell how synthetic lethality will be integrated intotherapeutic approaches.

کلیدواژه ها:

Breast Cancer ، Prostate Cancer ، Lung Cancer ، Colon Cancer ، Gastric Cancer ، Colorectal Cancer ، Blood Cancer ، Skin Cancer ، Ovarian Cancer ، Cervical Cancer ، Cervical Cancer ، Stomach Cancer ، Cancer Prevention ، Gene and Cancer ، Cell and Cancer ، Cancer Genetics ، Cancer Treatment and Management ، Chemotherapy