Identification of a predictive biomarker for response to CPT-11 in wild type p53 bronchogenic carcinoma cell lines

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Cytotoxic chemotherapy continues to be ineffective for treatment of bronchogenic carcinoma (BC). This is due, in part, to substantial inter-tumor variation in intrinsic or acquired resistance to available agents. For example, CPT-11 (irinotecan) induces a significant response in small cell lung carcinoma (SCLC) along with cisplatin in clinical trials. However, there are no proven clinical tests to predict CPT-11 resistance in a particular tumor. Although tumors with wild type p53 may be more responsive to chemotherapy, altered expression of one or more genes comprising the p53 pathway may cause variation in drug response by compromising apoptosis. In this study, we assessed the p53 transcriptional response to DNA damage by measuring apoptosis and transcript abundance levels of fifteen p53-associated genes at baseline and following treatment with camptothecin (CPT) in six cell lines that maintain wild type p53. Twenty-four hours following treatment, apoptosis was induced to varying levels and BCL2 transcript abundance was decreased in all cell lines, while the levels of p53-regulated genes CDKN1A, GPX1, CASP1, and PTGS2 were increased in some lines but not others. In an effort to identify a clinically relevant biomarker for resistance to CPT-11, baseline levels of three genes, TP73, MYC, and BCL2 were combined into the interactive transcript abundance index (ITAI), (MYC x TP73)/BCL2 which was inversely correlated with CPT-11 IC₅₀ and was positively correlated with apoptosis levels at baseline. These results demonstrate the variability of the p53 transcriptional response to DNA damage induced by cytotoxic chemotherapy in a subset of BC that maintain wild type p53. In addition, the association of the (MYC x TP73)/BCL2 ITAI with CPT-11 response and apoptosis levels in vitro justifies further experimentation on primary BC specimens in which p53 status is known. J.C.W. has a significant financial interest in Gene Express, Inc., which commercially manufactures reagents and protocols for StaRT-PCR.