Predicting Resistance
To understand more about what is driving this resistance, Dr Dev and colleagues first used CRISPR-Cas9 gene editing to screen breast cancer cells for the BRCA1 mutation and identify which genes drive resistance. Two proteins were identified (C20orf196 and FAM35A) that produce a protein complex referred to as shieldin (SHLD1/2). They found that when the level of shieldin in cells is depleted, tumor cells regain the ability to perform HR, rendering PARP inhibitors ineffective.
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“Shieldin, therefore, shields the DNA ends, acting as a barrier to perform HR,” Dr Dev explained. “Normally BRCA1 exists to remove that barrier for accurate repair, but in the absence of BRCA1, shieldin is enough to prevent HR. It is only when there is a mutation in shieldin that cells deficient in BRCA1 are able to perform HR.”
Dr Dev and colleagues took biopsies from patients with breast cancer who had BRCA1 mutations and transplanted the tissue into mice; the mice were treated with the PARP inhibitor olaparib to evaluate tumor responsiveness.
“Those tumors that harbored low levels of shieldin before treatment were all resistant [to olaparib],” Dr Dev said. “It is not possible to infer causation here, but in tandem with other work, this strongly leads us to believe that establishing the shieldin status of patients with a BRCA1 mutation could be useful.”
Next, Dr Dev and colleagues were able to see that BRCA1/shieldin double mutant cells, while resistant to olaparib, were highly sensitive to other treatments such as chemotherapy and radiotherapy.
“That means that in theory, it not only makes sense to avoid olaparib if a patients has a mutation in shieldin, but that [the patient] might instead benefit from certain alternative treatments,” Dr Dev said.
Given the frequency of resistance to PARP inhibitors, Dr Nussenzweig said that through basic research, this discovery could be clinically relevant in the future — and could suggest a potential mechanism by which resistance occurs.
“Now one has to look at patients and see whether or not this does happen,” Dr Nussenzweig said. “And, if so, figure out a way to get around it.”
References
- Gupta R, Somyajit K, Narita T, et al. DNA repair network analysis reveals Shieldin as a key regulator on NHEJ and PARP inhibitor sensitivity. Cell. 2018;173(4):972-988.
- Noordermeer SM, Adam S, Setiaputra D, et al. The shieldin complex mediates 53BP1-dependent DNA repair. Nature. 2018;560:117-121.
- Dev H, Chiang TW, Lescale C, et al. Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells. Nat Cell Biol. 2018;20(8):954-965.
