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With increasing uses of poly( ADP ‐ribose) polymerase ( PARP ) inhibitors ( PARP i) for cancer therapy, understanding their resistance is becoming urgent. However, acquired  PARP i resistance in the phosphatase and tensin homolog ( PTEN )‐deficient background is poorly understood. We generated 3  PARP i‐resistant  PTEN ‐deficient glioblastoma U251 variants separately with olaparib (U251/ OP ), talazoparib (U251/ TP ) and simmiparib (U251/ SP ). These variants displayed consistent resistance (2.46‐71.78‐fold) to all 5  PARP i, including niraparib and rucaparib, and showed higher degrees of resistance to the  PARP i to which the parental cells were more sensitive. The resistance was characteristic of fast emergence and high stability. However, the resistance acquirement did not cause an increasingly aggressive phenotype. The resistance was not correlated to various factors, including   PTEN   mutations. The  PARP i‐treated variants produced less γH2 AX  and G2/M arrest. Consistently, loss of 53 BP 1 occurred in all variants and its compensation enhanced their sensitivity to  PARP i by approximately 76%. The variants revealed slightly different cross‐resistance profiles to 13 non‐ PARP i anticancer drugs. All were resistant to Ara‐C (6‐8‐fold) but showed differential resistance to 5‐fluorouracil, gemcitabine and paclitaxel. Almost no resistance was observed to the rest drugs, including cisplatin.  SAMHD 1 was overexpressed in all the variants and its knockout completely restored their sensitivity to Ara‐C but did not affect their  PARP i sensitivity. The present study demonstrates a consistent resistance profile to  PARP i and a unique cross‐resistance profile to non‐ PARP i drugs in different  PARP i‐resistant U251 cells and reveals 53 BP 1 loss and  SAMHD 1 overexpression as the primary mechanisms responsible for their resistance to  PARP i and Ara‐C, respectively. These effects probably result from heritable gene change(s) caused by persistent  PARP i exposure.

cancer science

Acquired resistance of phosphatase and tensin homolog‐deficient cells to poly(ADP‐ribose) polymerase inhibitor and Ara‐C mediated by 53BP1 loss and SAMHD1 overexpression