BRCA Mutant Tumors

SYNTHETIC LETHALITY OF INHIBITING PARP-1 AND PARP-2 IN BRCA MUTANT TUMORS 

Two groups demonstrated that BRCA-1- and BRCA-2-deficient cells are acutely sensitive to PARPi [11,12]. Potent inhibitors like KU0058684 (5), KU0058948 (6), and AG14361 (26) were cytotoxic at nanomolar concentrations in HR-defective cells, and displayed excellent selectivity for BRCA-1- and BRCA-2-deficient cells over wild-type cells. After 24 h of exposure, 5 elicited G2 or M phase cell cycle arrest and a tetraploid DNA content. The applicability of this discovery was revealed when BRCA-2-deficient and BRCA-2-proficient cells were injected into mice and tumors were allowed to develop. Daily treatment with 5 or 26 had no effect on the BRCA-2 wild-type cells however, when BRCA-2-deficient cells were treated with PARPi, no tumors developed. 

To evaluate PARP inhibition in a realistic setting, olaparib (7) was tested in a BrcflI / p53 / mouse breast cancer model. Treatment with olaparib caused tumor growth inhibition without generating signs of toxicity [14]. Interestingly, upon cessation of treatment and tumor 

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