Cancer cells live their lives on the brink. Their rapid rate of growth, coupled with other unusual aspects of their biology, can place extraordinary demands on the cells,1 including their so-called housekeeping functions — mundane but essential processes that are necessary for the vitality of all cells, both healthy and cancerous.
DNA Damage Response
Here at Merck KGaA, Darmstadt, Germany, we are actively studying these critical functions, in particular the one known as the DNA damage response, or DDR. While DNA is often thought to be very stable and durable, it’s actually quite vulnerable. That’s why cells are equipped with the DDR — a highly sophisticated system that protects DNA from a range of attacks, both internal and external, which can harm the double helix. Such harm can take a plethora of forms, from minor tweaks, to wholesale changes in the genetic code, to complete breakage of the DNA backbone.2
In order to prevent these molecular injuries, the DDR harnesses a multiplicity of mechanisms to recognize DNA damage, repair it, and coordinate with other cellular processes, like proliferation, which may need to adjust while DNA is restored to a healthy state.2 Importantly, there is increasing evidence that many cancers harbor deficiencies in the DDR, and that exploiting those deficiencies can be an effective way to eliminate tumors — like an arrow aimed at Achilles’ heel.3
Specific inhibition to spare healthy cells
That is why our team is doing research on the inhibition of specific components of the DDR, with the goal of killing cancer cells, while at the same time, sparing normal, healthy cells. Currently, we are investigating inhibitors which target different aspects of the DDR, including the DNA repair enzymes DNA-PK, ATR, and ATM. Just as there are different types of DNA damage, there are distinct, and sometimes overlapping, methods for DNA repair.
For example, we are investigating the pathways responsible for mending double-strand breaks — a form of DNA damage that is lethal to cells if left unrepaired4. Given these breaks’ potency, it is not surprising that cells possess multiple ways of fixing them. Yet it is precisely because double-strand breaks are so detrimental that blocking their repair — intentionally letting them linger — signifies a promising anti-cancer approach.5
Early cause for optimism
I am passionate about targeting the DDR because it represents a powerful new therapeutic strategy in cancer. While our team is working toward a clinical proof of concept, there is some early cause for optimism. The first-ever DDR inhibitors are now on the market: a class of drugs known as PARP inhibitors, which are approved for use in certain patients with breast and ovarian cancer. The drugs are also being studied for the potential treatment of a variety of other cancers. These are tantalizing signs of the power of DDR inhibitors — signs that hopefully will only be further amplified in the coming years through our own efforts here at Merck KGaA, Darmstadt, Germany.
1 Cell division and cancer. Scitable by Nature Education. Available at: https://www.nature.com/scitable/topicpage/cell-division-and-cancer-14046590 Last accessed 16 May 2019
2 KAT Naipal, DC van Gent. PARP Inhibitors: The Journey From Research Hypothesis to Clinical Approval. Personalized Medicine. 2015;12(2):139-154 Available at: https://www.medscape.com/viewarticle/8420724 Last accessed 16 May 2019
3 J De Lartigue. Targeting Cancer’s Achilles Heel: DNA Damage Response Networks Beyond PARP. OncLive, published 26.12.2018. Available at: https://www.onclive.com/publications/oncology-live/2018/vol-19-no-24/targeting-cancers-achilles-heel-dna-damage-response-networks-beyond-parp Last accessed 16 May 2019
4 R Ceccaldi, B Rondinelli, A D.D’Andrea. Repair Pathway Choices and Consequences at the Double-Strand Break. Trends in Cell Biology, Volume 26, Issue 1, January 2016, Pages 52-64. Available at: https://www.sciencedirect.com/science/article/pii/S0962892415001427#! Last accessed 16 May 2019
5 M Srivastava, S C.Raghavan. DNA Double-Strand Break Repair Inhibitors as Cancer Therapeutics. Chemistry and Biology. Volume 22, Issue 1, 22 January 2015, Pages 17-29. Available at: https://www.sciencedirect.com/science/article/pii/S1074552114004220#! Last accessed 16 May 2019