BRCA1/Shieldin Double Mutations May Signal Resistance to PARP Inhibitors

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Double mutants may predict resistance to PARP inhibitors and could also indicate sensitivity to alternative treatments.
Double mutants may predict resistance to PARP inhibitors and could also indicate sensitivity to alternative treatments.

A newly identified protein complex called shieldin — named  because it shields the ends of broken DNA — regulates  DNA repair and is thought to play a role in the development of resistance to poly–(adenosine diphosphate–ribose) polymerase (PARP) inhibitors in BRCA1-deficient cells, according to the results of several studies published in recent months.1,2,3

One of the most recent studies by researchers from the Wellcome/Cancer Research UK Gurdon Institute also confirmed that tumors transplanted into mice with BRCA1 mutations and low levels of shieldin did not respond to PARP inhibitors; furthermore, tumors that gained resistance to PARP inhibitors also expressed lower levels of shieldin.3 This depletion of shieldin and PARP inhibitor resistance, consequently, may make those same cancer cells more sensitive to alternative cancer treatments, according to the study's lead author, Harveer Dev, MA, MD, academic fellow, the Wellcome Trust at the University of Cambridge in England.

“What this means is that, in principle, it may not only make sense to avoid [the PARP inhibitor] olaparib if the patient has a mutation in shieldin, but [the individual] might instead benefit from alternative treatments like chemotherapy or radiotherapy,” Dr Dev said. “That needs further validation in larger patient cohorts, but it points in the direction that we could begin to prognosticate and stratify based on this factor.”

DNA Repair

DNA double-helix breaks, or double-strand breaks (DSB), lead to cell death; however, there are 2 main methods to repair this damage. The faster, but less accurate, method is nonhomologous end-joining (NHEJ), which essentially sticks together the broken DNA strands. The second method is homologous recombination (HR). HR is a more accurate method; it uses a copy of DNA as a reference to fill in any missing gaps in the damaged DNA. NHEJ and HR cannot both be performed on the same DSB.

One protein required for HR is BRCA1. In the healthy cells of people who have BRCA1 mutations, HR can still occur because although there is 1 mutated copy of BRCA1, there is a second BRCA1 copy available to carry out HR. However, in cancer cells, there is no good copy of BRCA1 and HR cannot be performed.

PARP inhibitors were developed based on the discovery that they generate a specific type of DNA lesion that requires an intact HR pathway — one that relies on the proper functioning of BRCA1 — to repair defects, explained Dr Dev.

“If you have a mutation in the BRCA1, which is an integral component of the HR repair pathway, and treat with a PARP inhibitor, the cell generates a lesion that, in the absence of BRCA1, they cannot repair and those cells die,” Dr Dev said.

BRCA1-negative cancer cells die while the surrounding healthy cells, which still have a second BRCA1 copy available, survive the treatment.

“In other words, PARP inhibitors would be toxic and kill cancer cells, but only cancer cells,” said Andre Nussenzweig, PhD, chief of the Laboratory of Genome Integrity at the National Cancer Institute's Center for Cancer Research. “Although PARP inhibitors are somewhat effective, they have not been the miracle they initially were thought to be because people inevitably develop resistance.”

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