Low ATM protein expression and depletion of p53 correlates with olaparib sensitivity in gastric cancer cell lines.
Small-molecule inhibitors of poly (ADP-ribose) polymerase (PARP) have shown considerable promise in the treatment of homologous recombination (HR)-defective tumors, such as BRCA1- and BRCA2-deficient breast and ovarian cancers. We previously reported that mantle cell lymphoma cells with deficiency in ataxia telangiectasia mutated (ATM) are sensitive to PARP-1 inhibitors in vitro and in vivo. Here, we report that PARP inhibitors can potentially target ATM deficiency arising in a solid malignancy. We show that ATM protein expression varies between gastric cancer cell lines, with NUGC4 having significantly reduced protein levels. Significant correlation was found between ATM protein expression and sensitivity to the PARP inhibitor olaparib, with NUGC4 being the most sensitive. Moreover, reducing ATM kinase activity using a small-molecule inhibitor (KU55933) or shRNA-mediated depletion of ATM protein enhanced olaparib sensitivity in gastric cancer cell lines with depletion or inactivation of p53. Our results demonstrate that ATM is a potential predictive biomarker for PARP-1 inhibitor activity in gastric cancer harboring disruption of p53, and that combined inhibition of ATM and PARP-1 is a rational strategy for expanding the utility of PARP-1 inhibitors to gastric cancer with p53 disruption.
Department of Biochemistry & Molecular Biology; University of Calgary; Calgary, Alberta, Canada; Southern Alberta Cancer Research Institute; University of Calgary; Calgary, Alberta, Canada.
Eiji
E
Kubota
Department of Biochemistry & Molecular Biology; University of Calgary; Calgary, Alberta, Canada; Southern Alberta Cancer Research Institute; University of Calgary; Calgary, Alberta, Canada.
Christopher T
CT
Williamson
Department of Biochemistry & Molecular Biology; University of Calgary; Calgary, Alberta, Canada; Southern Alberta Cancer Research Institute; University of Calgary; Calgary, Alberta, Canada.
Ruiqiong
R
Ye
Southern Alberta Cancer Research Institute; University of Calgary; Calgary, Alberta, Canada; Tom Baker Cancer Center; Calgary, Alberta, Canada.
Anifat
A
Elegbede
Southern Alberta Cancer Research Institute; University of Calgary; Calgary, Alberta, Canada; Tom Baker Cancer Center; Calgary, Alberta, Canada.
Lars
L
Peterson
Department of Biochemistry & Molecular Biology; University of Calgary; Calgary, Alberta, Canada; Southern Alberta Cancer Research Institute; University of Calgary; Calgary, Alberta, Canada.
Susan P
SP
Lees-Miller
Southern Alberta Cancer Research Institute; University of Calgary; Calgary, Alberta, Canada; Tom Baker Cancer Center; Calgary, Alberta, Canada.
D Gwyn
DG
Bebb
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011753:Pyrones / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; D000970:Antineoplastic Agents; D009025:Morpholines; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011753:Pyrones; D016159:Tumor Suppressor Protein p53; D064007:Ataxia Telangiectasia Mutated Proteins; C531550:olaparib
ATM; PARP-1 inhibitor; gastric cancer; olaparib; p53