Mutations in the p53 tumor suppressor gene, a transcription factor activated by a variety of cellular stresses, including, those inflicted by anti-cancer agents, is a common genetic abnormality in GBMs. Although, p53 is involved in critical cellular processes, such as, cell cycle arrest, DNA repair and apoptosis, studies of p53 in tumor drug resistance and/or patient response to therapy have yielded mixed results. Thus, in gliomas and other cancers, such as, breast, bladder, and ovarian carcinomas, some studies have associated wild-type p53 with higher tumor drug resistance, while other studies indicate that mutant or functionally inactive p53, rather than wt p53, confers drug resistance. These observations indicate the significant complexity of the role of p53 in tumor response to therapy and suggest that other factors, including, downstream p53 pathways and/or regulation, may be important determinants of the p53 effects on the tumor drug resistance phenotype. We previously reported that the human GSTP1 gene, that encodes a major drug metabolizing protein, cell signaling regulator and a mediator of tumor drug resistance, is transcriptionally activated by p53 via a canonical p53 binding motif located in intron 4 of the GSTP1 gene. Our goal, in this study, is to gain further insight into the relationship between p53-dependent transcriptional control of GSTP1 in GBM and the extent to which it contributes to GSTP1 expression in primary patient tumor and, ultimately, to their response to therapy. For this, we sequenced the p53 gene across exons 2-11 in 42 primary GBM specimens quantified the level of GSTP1 gene expression by RNA-PCR and genotyped the allelic variants in them. The results showed, approx. half of the tumors to harbor wild-type p53. In those with mutant p53, the mutations spanned the entire p53 target region, the majority in the core DNA binding domain with the hot spots in codons 55, 72, 175, 245, 248, and 273. GSTP1 expression was significantly heterogeneous between the tumors, and with a few exceptions, correlated directly with the presence of wild-type p53. In representative tumors, the high GSTP1 gene expression was associated with resistance to cisplatin and temozolomide. These result suggest that, in GBM, transcriptional activation of GSTP1 by wild-type, and some mutant forms of p53, contributes to their resistance to therapy. Supported by NIH grants RO1 CA 153050, RO1CA127872, RO1 CA 112519, P50CA108786 and P30-CA14236.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1177. doi:1538-7445.AM2012-1177