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.

Abstract

With increasing uses of poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) for cancer therapy, understanding their resistance is becoming urgent. However, acquired PARPi resistance in the phosphatase and tensin homolog (PTEN)-deficient background is poorly understood. We generated 3 PARPi-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 PARPi, including niraparib and rucaparib, and showed higher degrees of resistance to the PARPi 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 PARPi-treated variants produced less γH2AX and G2/M arrest. Consistently, loss of 53BP1 occurred in all variants and its compensation enhanced their sensitivity to PARPi by approximately 76%. The variants revealed slightly different cross-resistance profiles to 13 non-PARPi 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. SAMHD1 was overexpressed in all the variants and its knockout completely restored their sensitivity to Ara-C but did not affect their PARPi sensitivity. The present study demonstrates a consistent resistance profile to PARPi and a unique cross-resistance profile to non-PARPi drugs in different PARPi-resistant U251 cells and reveals 53BP1 loss and SAMHD1 overexpression as the primary mechanisms responsible for their resistance to PARPi and Ara-C, respectively. These effects probably result from heritable gene change(s) caused by persistent PARPi exposure.

• Authors: Yu-Ting Wang, Bo Yuan, Hua-Dong Chen, Lin Xu, Yu-Nan Tian, Ao Zhang, Jin-Xue He, Ze-Hong Miao
• Journal: Cancer science (Cancer Sci) Vol. 109 Issue 3 Pg. 821-831 (Mar 2018) ISSN: 1349-7006 [Electronic] England
• PMID: 29274141 (Publication Type: Journal Article)
• Copyright: © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Antineoplastic Agents
• Phthalazines
• Piperazines
• Poly(ADP-ribose) Polymerase Inhibitors
• TP53BP1 protein, human
• Tumor Suppressor p53-Binding Protein 1
• simmiparib
• Cytarabine
• talazoparib
• PTEN Phosphohydrolase
• PTEN protein, human
• SAM Domain and HD Domain-Containing Protein 1
• SAMHD1 protein, human
• olaparib

Topics

• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cytarabine (pharmacology)
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic (drug effects)
• Glioblastoma (drug therapy, genetics)
• Humans
• PTEN Phosphohydrolase (deficiency, genetics)
• Phthalazines (pharmacology)
• Piperazines (pharmacology)
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology)
• SAM Domain and HD Domain-Containing Protein 1 (genetics)
• Tumor Suppressor p53-Binding Protein 1 (genetics)