UT Health San Antonio researchers have discovered a novel way to kill cancers that are caused by an inherited mutation in BRCA1, the type of cancer for which actress Angelina Jolie had preventive double mastectomy and reconstructive surgery in 2013.
“This represents a new treatment for inherited breast and ovarian cancer, which are higher in our region,” said Robert A. Hromas, M.D., FACP, professor and dean of the Joe R. and Teresa Lozano Long School of Medicine at UT Health San Antonio. Dr. Hromas is senior investigator on the research, published in the journal Proceedings of the National Academy of Sciences. (Reference: “MiR223-3p promotes synthetic lethality in BRCA1-deficient cancers,” Aug. 8, 2019.)
A tiny molecule called microRNA (miR) 223-3p prevents normal cells from making mistakes while repairing their DNA.
However, cancers with BRCA1 mutations repress miR223-3p to permit their cells to divide.
Adding back miR223-3p forces the BRCA1-mutant cancer cells to die, said study co-author Patrick Sung, D. Phil. Dr. Sung, who joined UT Health San Antonio in 2019 from Yale, is a BRCA1 cancer expert who occupies the Robert A. Welch Distinguished Chair in Biochemistry.
Exploiting the cancer’s Achilles’ heel
MiR223-3p acts like a light switch, turning off proteins that BRCA1-mutant cancers need to divide properly.
Without these key cell division proteins, BRCA1-mutant tumors commit suicide, Dr. Hromas said.
“It’s kind of a cool way of thinking about treatment,” Dr. Hromas said. “We are using the very nature of these BRCA1-deficient cancer cells against them. We are attacking the very mechanism by which they became a cancer in the first place.”
There is evidence that restoring miR223-3p before cells convert to cancer can even prevent BRCA1-related disease, he said.
BRCA gene mutations affect 1 in every 400 people in the United States—an estimated 825,000. After Ashkenazi Jews, Hispanics have the second-highest prevalence of BRCA1 disease-causing mutations.
The disease’s burden in San Antonio and South Texas is therefore among the highest in the country.
DNA replication is not a smooth and continuous process, but rather prone to interruptions (1, 2).
DNA damage or nucleotide depletion can induce stalling of the replication machinery (3, 4), which can result in replication stress and subsequent fork collapse, with disassociation of the replication apparatus (5, 6).
As such, replication stress is a common etiology of genomic instability, resulting in either cell death or neoplastic transformation (4, 6⇓–8).
HR is the most common pathway for stressed replication fork repair and restart (5, 7, 8).
The rate-limiting step in HR is the nucleolytic resection of the 5′ strand at a DNA free end, initiated when BRCA1/CtIP replaces 53BP1/RIF1/Shieldin at the site of DNA damage (9⇓⇓–12). After 5′ strand resection (13⇓⇓–16), BRCA2 then loads the RAD51 recombinase onto the 3′ single-stranded DNA for invasion of the sister chromatid (17⇓–19), which results in Holliday junction formation that is later resolved by MUS81 and SLX4 (20, 21).
Germline or acquired mutations in BRCA1 or its interacting partner BAP1 result in defects in the HR pathway, and subsequent replication fork instability and oncogenesis (22⇓⇓–25). HR-deficient cancers become addicted to other repair pathways to resolve replication fork stress such as aNHEJ (26⇓⇓⇓–30).
This addiction is a singular weakness of these cancer cells, and can be targeted with therapeutic agents (8, 25, 29, 30), generating synthetic lethality. This synthetic lethality underlies the efficacy of PARP1 inhibitors in breast, ovarian, and prostate cancers that harbor inherited or acquired mutations in BRCA1 (31, 32).
PARP1 can initiate aNHEJ by displacing the Ku complex from the DNA double-strand break (33, 34). CtIP, Pso4, and Mre11 then mediate limited 5′ end resection, followed by DNA polymerase theta promoting microhomology annealing (27⇓–29).
DNA ligase 1 or 3 with XRCC1 then promote ligation of the free DNA ends (27, 33). Pharmacologic inhibitors of PARP1 lock it onto DNA, generating obstacles that stall replication forks, which in BRCA1- or BAP1-mutant cells cannot be repaired by HR (31, 32, 35).
PARP1 inhibition also prevents the use of the aNHEJ back-up repair pathway to resolve the replication forks stalled by PARP1 locked on DNA, resulting in fork collapse and cell death (8, 25, 27). While aNHEJ promotes repair of stressed replication forks in BRCA1/BAP1-defective cells, it comes at a cost; aNHEJ can mediate chromosomal translocations (33, 34).
This occurs when aNHEJ erroneously anneals and then ligates free DNA ends on distinct chromosomes (26, 33, 34).
The three FDA-approved PARP1 inhibitors, olaparib, rucaparib, and niraparib, have each shown impressive response rates in HR-deficient cancers (36⇓⇓⇓⇓–41). However, these agents can occasionally lead to myelodysplastic syndrome, and resistance can develop (30, 41, 42).
In this study, we found that the microRNA species miR223-3p is a negative regulator of aNHEJ, likely to restrain aNHEJ from generating aberrant chromosomal translocations that would lead to genomic instability. Importantly, we discovered that cancer cells deficient in HR repress miR223-3p strand selection and instead express miR223-5p. Reconstituting expression of miR223-3p is synthetically lethal to BRCA1- and BAP1-defective cancer cells, demonstrating its potential as an effective cancer therapeutic agent.
More information: Gayathri Srinivasan et al, MiR223-3p promotes synthetic lethality in BRCA1-deficient cancers, Proceedings of the National Academy of Sciences (2019). DOI: 10.1073/pnas.1903150116
Journal information: Proceedings of the National Academy of Sciences
Provided by University of Texas Health Science Center at San Antonio
