(Philadelphia, PA) – Proteins commonly known as BRCA – short for BReast CAncer susceptibility gene- serve a critical role in cellular DNA repair, but when mutated they allow genetic errors to replicate, facilitating cancer development. If the BRCA repair system is disabled in cancer cells, the cells simply turn to backup repair mechanisms and adapt to alternative repair pathways, a survival mode that also underlies their ability to evade targeted drug therapies.
Now, new research by scientists at the Lewis Katz School of Medicine at Temple University (LKSOM) shows that it is possible to eliminate at least two backup repair mechanisms at the same time using two targeted therapies. The strategy effectively narrows down the number of secondary repair pathways available, helping to ensure cancer cell eradication.
The novel approach, described June 12 in a paper published in Cell Reports, is named dual synthetic lethality, so-called because cancer cell death is induced by two drugs targeting distinct DNA repair pathways at the same time. "Cancers cells have multiple ways of protecting themselves from death," explained senior investigator Tomasz Skorski, MD, PhD, Professor of Microbiology and Immunology and Associate Professor at the Fels Institute for Cancer Research and Molecular Biology at LKSOM.
Tumor cells that carry BRCA-deficiency mutations frequently rely on DNA repair mediated by a protein known as PARP1. Clinically, PARP1 inhibition can significantly improve progression-free survival in patients with cancers involving hereditary BRCA mutations.
Over time, however, the effectiveness of PARP1 inhibition declines, and cancer relapses. According to Dr. Skorski, this happens because targeting one pathway is not enough. "The tumor cells eventually escape PARP1 inhibition by activating another backup to the BRCA-mediated repair pathway," he said. "Our previous work had suggested that RAD52-dependent pathways are a likely escape route, which led us to see whether simultaneous inhibition of both PARP1 and RAD52 could trigger more effective lethality."
Dr. Skorski's team first tested their idea in a series of experiments in BRCA-deficient solid tumor and leukemia cell lines in vitro. Using an experimental RAD52 inhibitor, they were able to show that RAD52 blockade enhanced synthetic lethal effects in cells treated with the PARP inhibitor olaparib, a drug approved by the Food and Drug Administration. For all tumor types, the dual treatment completely eradicated BRCA-deficient tumor cells.
The simultaneous targeting strategy was then tested against BRCA-deficient tumors in mice, in which the researchers recapitulated the effects of BRCA deficiency in breast cancer and in acute and chronic myelogenous leukemia. They found that dual inhibition exerted strong effects against tumors in vivo, showing greater activity than either agent alone.
Importantly, the teams' experiments showed, both in vitro and in vivo, that normal cells, with normal BRCA activity, are unaffected by the dual treatment. "Normal cells continue to use BRCA-mediated repair as their primary DNA repair pathway and do not rely heavily on PARP1 or RAD52," explained Katherine Sullivan-Reed, a graduate student in Dr. Skorski's research laboratory and first author on the new paper. Leaving normal cells relatively unharmed helps limit the severity of side effects patients may experience with targeted cancer therapy.
The new research provides a foundation for pursuing the development of a clinically viable drug to inhibit RAD52, as well as the development of a screening test specifically for patients who carry tumors displaying BRCA-deficiency.
In the near-term, Dr. Skorski's team also plans to continue investigating alternative DNA repair pathways, which are essential for tumor cells but expendable in normal cells. "One of our primary goals is to find additional targets to kill cancer cells, without increasing toxicity," he added.
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Other researchers contributing to the multi-center, multi-national study include Elisabeth Bolton-Gillespie, Yashodhara Dasgupta, Samantha Langer, Micheal Siciliano, Margaret Nieborowska-Skorska, and Morgan Moore, Department of Microbiology and Immunology, Fels Institute for Cancer Research and Molecular Biology, LKSOM; Kritika Hanamshet and Alexander V. Mazin, Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia; Elizaveta A. Belyaeva and Mariusz A. Wasik, Department of Pathology and Laboratory Medicine, University of Pennsylvania; Andrea J. Bernhardy and Neil Johnson, Molecular Therapeutics Program, Fox Chase Cancer Center; Jaewong Lee and Markus Müschen, Department of Systems Biology, Beckman Research Institute, Monrovia, Calif.; Huaqing Zhao, Department of Clinical Sciences, LKSOM; Peter Valent, Department of Internal Medicine I, Division of Hematology and Hemostaseology, Ludwig-Boltzmann Cluster Oncology, Medical University of Vienna, Austria; Ksenia Matlawska-Wasowska, Division of Pediatric Research, Department of Pediatrics, University of New Mexico Health Sciences Center; Smita Bhatia, Department of Pediatrics, University of Alabama Birmingham; Ravi Bhatia, Division of Hematology-Oncology, Department of Medicine, University of Alabama Birmingham.
The research was funded by National Institutes of Health grants R01 CA186238, R01 CA188347, P30 CA056036, R01 CA214799, and F31 CA203161 and by the Drexel Coulter Program Award and U.S. Department of Defense grant OC130212.
About Temple Health
Temple University Health System (TUHS) is a $2.1 billion academic health system dedicated to providing access to quality patient care and supporting excellence in medical education and research. The Health System consists of Temple University Hospital (TUH), ranked among the "Best Hospitals" in the region by U.S. News & World Report; TUH-Episcopal Campus; TUH-Northeastern Campus; Fox Chase Cancer Center, an NCI-designated comprehensive cancer center; Jeanes Hospital, a community-based hospital offering medical, surgical and emergency services; Temple Transport Team, a ground and air-ambulance company; and Temple Physicians, Inc., a network of community-based specialty and primary-care physician practices. TUHS is affiliated with the Lewis Katz School of Medicine at Temple University, and Temple University Physicians, which is Temple Health's physician practice plan comprised of more than 500 full-time and part-time academic physicians in 20 clinical departments.
The Lewis Katz School of Medicine (LKSOM), established in 1901, is one of the nation's leading medical schools. Each year, the School of Medicine educates approximately 840 medical students and 140 graduate students. Based on its level of funding from the National Institutes of Health, the Katz School of Medicine is the second-highest ranked medical school in Philadelphia and the third-highest in the Commonwealth of Pennsylvania. According to U.S. News & World Report, LKSOM is among the top 10 most applied-to medical schools in the nation.
Temple Health refers to the health, education and research activities carried out by the affiliates of Temple University Health System (TUHS) and by the Katz School of Medicine. TUHS neither provides nor controls the provision of health care. All health care is provided by its member organizations or independent health care providers affiliated with TUHS member organizations. Each TUHS member organization is owned and operated pursuant to its governing documents.
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http://dx.doi.org/10.1016/j.celrep.2018.05.034
