Abstract 4596: Missense mutations in the p53 DNA-binding motifs (DBMs) are associated with shorter time to progression (TTP) in erlotinib-treated, EGFR-mutated patients

Autor: Miguel Angel Molina, Clara Mayo, Carlos Camps, Enric Carcereny, Rafael Rosell, Jordi Bertran-Alamillo, Susana Benlloch, Miquel Taron, Bartomeu Massuti, Santiago Viteri
Rok vydání: 2012
Předmět:
Zdroj: Cancer Research. 72:4596-4596
ISSN: 1538-7445
0008-5472
Popis: Background: Advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations has an average time to progression (TTP) of 14 months (mo) and overall survival of 27 mo when treated with erlotinib. However, EGFR mutations can only imperfectly predict outcome. In NSCLC cell lines, tyrosine kinase inhibitors (TKIs) induce p53 translocation from the cytoplasm to the nucleus and subsequent up-regulation of Fas and caspase activation leading to apoptosis. This mechanism was defective in p53-null cells. We tested whether mutations in the TP53 gene influence outcome to erlotinib in EGFR-mutated patients (p). Expression levels of the p53 repressor MDM2 were also examined. Methods: We assesed p53 status in pretreatment paraffin-embedded tumor samples from 93 erlotinib-treated, EGFR mutated advanced NSCLC p. Mutations in exons 5, 6, 7 and 8 were screened by High Resolution Melting analysis (HRM) followed by sequencing of the amplified products with non-wild type melt curves. All mutant samples were re-confirmed by standard PCR and sequencing. Expression levels of MDM2 mRNA were determined by quantitative RT-PCR. Results: Mutations in exons 5-8 of the TP53 gene were detected in 26 of 93 p (28%). We found an unusually high frequency of in-frame and frameshift deletions (23% of mutations), indicating that the spectrum of p53 mutations might be different in EGFR-mutated NSCLC. Mutations in the TP53 gene were not associated with sex, age, smoking status, histology, exon 19 vs. 21 mutation, or response, but, within the study population, were significantly less frequent in p with ECOG 2 or above. The mutations were also associated with the presence of the pretreatment T790M mutation. 14 p had mutations in one of the p53 DNA binding motifs (DBMs), and showed TTP to erlotinib of only 9 mo, compared to 19 months for wt p and 27 mo for those carrying a non-DBM mutation. Survival was 24 mo vs. 31 mo, and not-reached, respectively. Finally, MDM2 mRNA levels were significantly lower in tumors with p53 mutations, especially when these affected DBMs. In the case of wt p, high MDM2 expression correlated with a better TTP and survival. Conclusions: TP53 mutations co-exist with EGFR mutations in a significant number of p; and those in the DBMs are associated with poorer response to erlotinib. This finding paves the way for the possibility of combining erlotinib with a drug restoring p53 function in those p harboring DBM mutations in the TP53 gene. 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 4596. doi:1538-7445.AM2012-4596
Databáze: OpenAIRE
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