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DNA Damage Response

Why target the DNA Damage Response to fight cancer ?

The therapeutic approach targeting the DNA Damage Response (or DDR) is a relatively new field in oncology. Its importance has been hailed by the scientific community by the awarding of the 2015 Nobel Price in Chemistry to three researchers for their studies on DNA repair mechanisms. Professor Tomas Lindahl, a joint recipient of this Nobel Prize, chairs the Onxeo Scientific Committee. The inhibition of DNA repair mechanisms in tumor cells is today recognized as one of the most promising ways of treating cancer.

It is based on the fact that cancer cells accumulate DNA breaks, either due to their uncontrolled proliferation, or following treatments such as chemo- or radiotherapy. Not being able to replicate with damaged DNA, their survival is highly dependent on the DNA repair mechanisms, which activate a complex cascade of proteins detecting, signaling and repairing the breaks. When these mechanisms are impaired, the cancer cells are deprived of the ability to repair their DNA, which leads to their death, when they try to replicate with a damaged DNA.

The DNA Damage Response (DDR)

DNA damage response is a sophisticated cascade of cellular events which can be summarized, in a very simplified manner, into three stages:

Detection and identification of the damage with “sensor” proteins such as PARP.
Signaling with “transducer” proteins such as DNA-PK, ATR, etc. whose role is essential in coordinating the most appropriate response, repair of the DNA break or destruction of the cell if the damage is too extensive.
Repair with effector proteins such as RAD, POLQ, etc. which will appropriately repair the DNA molecule (resection, replication, insertion, etc.).


Learn more about DDR in AsiDNA™ Letter No 1

Today, many drugs aim at impairing the DNA repair process of tumors cells by inhibiting one of the key proteins of the DNA Damage Response. While this approach has already demonstrated substantial benefits in some cancer types (read about PARP inhibitors below), these targeted therapies always meet with resistance after repeat treatment: cancer cells use alternate proteins and pathways to repair their broken DNA and treatments are no longer effective over time.

The DNA repair inhibitors’ market was initially invested by the PARP inhibitors, one of the DNA damage response proteins, with the approval of the AstraZeneca product olaparib (Lynparza®) in advanced ovarian cancer at the end of 2014. PARP inhibitors  continue to extend the field of their indications with clinical trials underway in broad indications such as lung or pancreatic cancer.

However, PARP inhibitors often depend on certain genetic mutations, particularly those of the BRCA genes and are faced over time with acquired resistance. Despite these limitations, PARP inhibitors have shown a real clinical benefit, particularly in ovarian cancer, with, for example for olaparib, a survival rate without progression higher than 60% after 3 years, compared to 27% after chemotherapy1.



The mechanism of action of AsiDNA™ does not require a particular genetic mutation to operate and is complementary to that of PARPi, thereby increasing their efficacy and reversing the resistance to their treatment.



OX401, the newest addition to our pipeline, is a next-generation PARP inhibitor via an agonist mechanism that does not induce resistance and activate the immune response.


1 Moore et al. N Engl J Med 2018; 379:2495-2505