Exploiting Liabilities in Mechanism of DNA Repair for Cancer Therapy

Dear Colleagues,

In recent times, seems to have been a great output of information on both the mechanisms of DNA repair and damage response, which has also led to the identification of novel strategies to individualized targeting of malignant cells by exploiting their intrinsic liabilities in such pathways.  This has resulted in novel clinical approaches to radio- and chemotherapy.

Radiotherapy and most forms of chemotherapy aim to inflict unrecoverable damage to DNA to eliminate malignant cells.  The central tenet of the strategy is that cancer cells, owing to their dysregulated proliferation capacity, should be much more susceptible to incurring the lethal genomic-altering effects of such therapies.  In practice, many malignant cells are more resistant to such therapies than the normal cells in many organs, or can become so, rendering these therapies wholly unactionable. To counter this, much effort has been dedicated to combating the common phenomenon of MDR in order to increase the targeted effectiveness of chemotherapy and increase the localized concentration of the drugs within the tumors.  Somewhat more recently, significantly more efforts have been dedicated to enhancing the damage inflicted by radio- and chemotherapies by interfering with the mechanisms of the DNA repair process itself, after the realization that many cancer cells have intrinsic liabilities in these, for example, by their propensity of inactivating checkpoint regulators or pro-apoptotic functions that are normally meant to curtail their unconstrained replication.  This has led to a renewed interest in the DNA damage repair processes to unveil specific liabilities that can be therapeutically targeted.  Perhaps the most famous example of this has been the advent of PARPis to target, via synthetic lethality, the most serious form of DNA damage: DSBs.  These can sometimes be repaired via two main processes: HRR (when a sister chromatid donor is available for recombinational repair) and NHEJ (a simpler but less precise process of rejoining the broken ends).  Frequently, cancer cells have reduced ability to repair DSBs via HRR, a phenomenon first described in BRCA-deficient cells and thus since known as BRCAness to encompass other deficient gene products involved in the process.  While such cells can often repair the DSBs (that can be induced by radio- and chemotherapy) via several alternative NHEJ mechanisms leading to their survival, if the NHEJ repair process is also targeted by therapy, e.g., by PARPis, this will result in what is known as a synthetic lethal outcome, whereby a second loss of function cannot be survived.  While this example has proven to be remarkably effective, at least for a significant DFS period for many types of cancers, it is certainly not a unique target, as much research has revealed many more liabilities in the DNA repair processes or in the DDR, which this special series aims to collect and display.

For this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following: mechanisms of DNA repair or damage response (DDR); specific liabilities of cancer cells when compared to normal tissues in the same areas; tumor suppressors related to DNA repair of DDR; and mechanisms of adaptation to persistent DNA damaging agents.

We look forward to receiving your contributions.

Dr. Arrigo De Benedetti
Dr. Mariarita de Felice
Dr. Mariarosaria de Falco
Guest Editors

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• mechanisms of DNA repair
• DDR
• targeted radio- and chemotherapies
• mechanisms of genotoxins tolerance/resistance
• synthetic lethality