Abstract A52: PTEN/PTENP1 transcripts expression and alterations in a large panel of human tumor xenograft in nude mice: Implication for resistance to targeted therapies involving EGFR/PI3K/PTEN pathways.

Background: PTEN alterations are major determinants of resistance to several new targeted therapies involving EGFR/PI3K/PTEN pathways. Recent findings also suggested implication of its associated PTENP1 pseudogene. PTEN can be altered at the gene or transcriptional level. PTEN expression is often higher in stroma than in tumor cells complicating readouts of assayed tumor samples. Taking advantage of the stroma of xenografted human tumors in nude mice being produced by the host, we characterized specific PTEN/PTENP1 tumor cell transcript expression levels and mutational status in a large panel of tumor models. Materials and Methods: A total of 192 patient-derived xenografts of 23 different histotypes were investigated. Human and murine PTEN, PTENP1 mRNA levels as well as PTEN gene copy numbers were quantified by quantitative polymerase chain reaction using species specific assays; PTEN transcript was analyzed by sequencing. Results were analyzed by tumor type and compared to sensitivity to cetuximab. Results: PTEN transcript alterations were observed in 32 of the 192 tumor xenografts (17%) and were shown to be due to loss of PTEN gene for 9, to loss of transcript expression for 4 and to frameshift or substitution-missense mutations for 14 and 7 samples, respectively. PTEN expression levels and alteration frequency were both associated with specific histotypes. Melanoma and breast cancer showed most PTEN alterations (6/11 and 6/16 respectively). PTENP1 pseudogene was shown to be well expressed in only 61% of tumor xenografts, whereby expression levels depended on the tumor type. No or low PTENP1 expression was found in tumor models having a PTEN alterations. Finally, in a tumor panel consisting of colon, non-small cell lung, gastric and head and neck cancer we found that none of the PTEN altered tumors analyzed were sensitive to cetuximab in vivo. Conclusion: This study confirmed the multiplicity of PTEN alterations occurring in cancer. PTEN expression levels and alterations were associated with PTENP1 expression levels and depended on tumor types. PTEN alterations were shown to be associated with tumor resistance to cetuximab and their impact on other targeted therapies involving EGFR/PI3K/PTEN pathways should be evaluated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A52.