“Shieldin” cancer from drugs: Major breakthrough in understanding resistance to cancer therapy

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This may be a key to understanding and counteracting cancer drug resistance. The discovery also sheds new light on how our body generates different types of antibodies.

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Breast cancer is one the most frequently occurring cancer in women worldwide, and hundreds of thousands of new cases are diagnosed with the disease every year. A sizeable portion of breast cancer is hereditary, meaning that a woman inherits faulty breast cancer causing genes from her parents. For example, mutations in BRCA1 gene are found in many cases of hereditary breast cancer. These women are what we call BRCA positive. Basically, the BRCA proteins are involved in fixing broken DNA in cell, and because BRCA mutant cells cannot accurately repair their DNA, it leads to development of cancer.

“What the shieldin does is that it acts as a molecular “shield” to protect broken DNA ends against the nuclease “swords”, and by doing so it aids in DNA repair,” adds Chuna Choudhary, who lead the research project at University of Copenhagen.

Understanding cancer drug resistance

A mutation in BRCA1 gene increases the risk of breast cancer so significantly that many women, such as the actress Angelina Jolie, have chosen to undergo preventive mastectomy to avoid getting breast cancer. In many countries healthcare providers offer women genetic tests to discover the risk early and provide prophylactic treatment. Fortunately, a new class of drugs, called PARP inhibitors, is highly effective in treating breast and ovarian cancer patients with faulty BRCA1. However, in some patients the drug is not effective, and in other cases patients become resistant to the drug after a period of treatment.

Researchers Discover New DNA Repairers

A research team, led by Chuna Choudhary and Jiri Lukas, at the Novo Nordisk Foundation Center for Protein Research at the Faculty of Health and Medical Sciences at the University of Copenhagen, have used advanced technology (mass spectrometry) to uncover previously unknown proteins that are involved in repairing damages to the DNA. To do this, they genetically engineered human cells to “tag” key proteins that were already known to repair DNA and looked at other proteins that interact with them.

“This is very similar to using social media, such as Facebook, for finding out interactions of a person. By analyzing social network profile of a person we can find links to the individuals he/she interacts with, but who are unknown to us.” says Rajat Gupta, who is the first author of the study. This sophisticated analysis of “networks of DNA repair” allowed the researchers to get a detailed map of DNA repairing proteins and to discover new ones.

New Protein Shield Affects Cancer Therapy

Due to the inherent risk of resistance to PARP inhibitors, researchers are therefore actively trying to understand the mechanisms that cause the resistance, and to find new targets that can be used to treat these resistant cancers.

Importantly, the new research has discovered a previously unknown group of proteins, which they have called Shieldin. “We have gained new, unique insight into protein networks of the DNA repair process and identified a new “protein shield” that protects broken DNA ends and thereby helps in repairing damaged DNA. Shieldin also affects treatment responses to PARP inhibitor drugs, that are among the most advanced and effective therapy for BRCA positive cancers. The new findings may contribute in making decisions for treating cancer patients and to understand the mechanisms of resistance to PARP inhibitor drugs,” says Professor Chuna Choudhary.

Although further studies are required to elucidate how exactly shieldin influences the development of cancer and the immune system, the researchers think that shieldin may have played a decisive role in the evolutionary leap that resulted in the development of adaptive immune systems, such as those of humans.

“The nurse shark is one of the earliest animals that have an antibody-based adaptive immune system like ours. Strikingly, this shark was the first animal that acquired the shieldin complex, indicating that emergence of shieldin may have represented a remarkable step in the evolution that allowed development of antibody-based advanced immune system in humans,” enlightens Professor Choudhary.

The next step will be to further understand details of the protein networks, how exactly shieldin protects DNA, and how it impacts cancer resistance to PARP inhibitor. Researchers will also be interested to assess whether shieldin could be used as a new cancer drug target. Read the entire study “DNA repair network analysis reveals shieldin as a key regulator of NHEJ and PARP inhibitor sensitivity” in Cell here.

The study was carried out at the Novo Nordisk Foundation Center for Protein Research (CPR) at the University of Copenhagen in close collaboration with the teams of Dr. Jiri Lukas and Niels Mailand at CPR, Dr. Andre Nussenzweig from NIH, and Dr. Michael Lammers from University of Cologne.