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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
“Synthetic lethality” is a term used to describe an extreme case of a genetic interaction in which two individual viable mutations combine to produce a lethal phenotype. In 1997 Hartwell and colleagues first proposed the use of synthetic lethality as a therapeutic strategy to be employed in cancers with genetic defects in their DNA-repair proteins, and also in cancers “addicted” to a particular DNA-repair mechanism. In this approach, a defect in one DNA-repair gene is combined with chemical inhibition of the activity of a second DNA-repair protein critical for the survival of cancer cells but less important for the survival of healthy cells.
BRCA Mutation and PARP Inhibitors
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Arjun Mittra, James H. Doroshow, Alice P. Chen
Though mutations in BRCA genes can lead to the development of cancer, the presence of such mutations also makes these cells more susceptible to cytotoxic injury from chemotherapy, particularly platinum analogs [9, 62]. Such cells are also more vulnerable to alterations in other DNA repair pathways leading to enhanced susceptibility to cell killing by complementary DNA damage pathways, so called “synthetic lethality” [18, 33].
Breast and ovarian cancer
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
There is now considerable evidence that BRCA-associated tumours are more sensitive to certain chemotherapeutic drugs, thanks to advances in the understanding of the biological function of the BRCA1/2 genes and the role of the BRCA1/2 proteins in DNA repair. The poly-ADP ribose polymerase (PARP) proteins also play important roles in DNA repair, and we now know that inhibiting PARP in the presence of BRCA deficiency leads to cell death, while cells with normal BRCA function remain unaffected. This concept, that the mutation or inhibition of two pathways can lead to cell death when mutation or inhibition of either alone would not, is termed synthetic lethality (see also Chapter 12).
Precision medicine for the treatment of triple negative breast cancer: opportunities and challenges
Published in Expert Review of Precision Medicine and Drug Development, 2021
Maaz Tahir Sadiq, Juliette Servante, Srinivasan Madhusudan
Numerous precision treatments, some discussed above, are in trials and the data generated suggests that their benefit is mostly in patients where synthetic lethality can be achieved. This encourages novel strategies combining multiple targeted treatments that complement each other to induce synthetic lethality at the risk of worse adverse effect profiles. Eventually, actionable targets most easily manipulated are likely to become scarce. Large multi-center trials able to recruit many patients should be designed as ‘umbrella’ studies (where interventions are matched with patients depending on baseline tumor genomic/immunogenic profile) to identify the ‘best interventions’. These can form the proof of concept basis required for larger trials with the best chance of success so momentum in TNBC management can continue.
Antibody-drug conjugates in metastatic triple negative breast cancer: a spotlight on sacituzumab govitecan, ladiratuzumab vedotin, and trastuzumab deruxtecan
Published in Expert Opinion on Biological Therapy, 2021
Julia E. McGuinness, Kevin Kalinsky
Another strategy under current investigation is the combination of SG with PARP inhibitors (PARPi), with the goal of inducing synthetic lethality. Synthetic lethality refers to the concept that simultaneous alteration of two genes or pathways required for cell growth or viability results in cell death [39]. In cancer cells with somatic or germline mutations causing alterations in one pathway, synthetic lethality is achieved by identifying and then inhibiting the pathway upon which the cells depend for viability. This concept has been exploited in patients with mTNBC pathogenic variants in BRCA1/2, which results in defective repair of double-stranded DNA breaks and therefore requires use of alternative pathways of DNA repair for cancer cell survival. PARP enzymes are involved in repair of single-stranded DNA breaks, and PARPi have shown efficacy and achieved FDA approval in patients with metastatic HER2- negative breast cancer, including mTNBC, who harbor pathogenic variants in BRCA1/2 [40].
Novel agents for mantle cell lymphoma: molecular rational and clinical data
Published in Expert Opinion on Investigational Drugs, 2020
Clémentine Sarkozy, Vincent Ribrag
MCL is a particular type of NHL carrying the hallmark t(11;14), leading to CCND1 overexpression and cell-cycle deregulation. These NHL are also characterized by frequent alteration in DNA damage response molecules such as ATM, conferring complex genomic abnormalities, and TP53. Among these genomic events, TP53 mutations have consistently been associated with a poor outcome and absence of response to chemotherapy. FDA approved targeted therapies are available and BTK inhibitors, proteasome inhibitors, or lenalidomide and combination with agents such as BCL2 inhibitors have already shown efficacy data. Widely applied in the relapse setting, these chemo-free strategies are being developed in first line with impressive results. Thanks to NGS technics, the mechanisms of resistance to these agents can be studied thus highlighting abnormalities within NF-kB alternative pathway and epigenetic regulators, or the crosstalk between the tumor cells and ME. Synthetic lethality approaches provide rational for the development of new therapeutic combinations (as some targeting DNA damage pathway and epigenetic) in the context of specific genomic alterations which are now being assessed in phase I trials.