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TP53 and additional pathways in therapy resistance
Breast Cancer Research volume 7, Article number: S.32 (2005)
Resistance to chemotherapy is the main obstacle to cancer cure. Despite encouraging results from preclinical studies, we have limited knowledge regarding mechanisms causing therapy resistance in vivo. We previously identified mutations affecting the L2 and/or L3 domains of the TP53 gene to predict resistance to anthracycline as well as mitomycin therapy [1, 2]. However, while TP53 mutations were significantly associated with therapy failure, we observed tumours resistant to therapy despite harbouring wild-type p53. We also saw responding tumours among those harbouring TP53 mutations affecting the L2 or L3 domains.
Based on these assumptions, we postulated that chemoresistance could be due to failure of the 'p53 pathway' acting in concert with one, or more, redundant pathways . In a recent paper we thus reported a mutation of the CHEK2 gene among one of the tumours resistant to therapy despite harbouring wild-type TP53 . In addition, we are searching for redundant pathways that may compensate for the p53 mechanism. Strikingly, looking at genetic alterations associated with resistance to other drugs with respect to other malignancies, this seems to concentrate on drugs known to be involved in so-called 'family cancer syndromes', meaning genes involved either in growth arrest, apoptosis or DNA damage repair . This may seem logical, as much of the damage created by chemotherapeutic drugs resemble genetic events involved in carcinogenesis. Thus, at this stage, our interest is focused on genetic pathways involving genes involved in 'family cancer syndromes'. An update of our current results will be presented.
Aas T, et al: Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nat Med. 1996, 2: 811-814. 10.1038/nm0796-811.
Geisler S, et al: TP53 gene mutations predict the response to neoadjuvant treatment with FUMI in locally advanced breast cancer. Clin Cancer Res. 2003, 9: 5582-5588.
Lønning PE: Genes causing inherited cancer as beacons identifying the mechanisms of chemoresistance. Trends Mol Med. 2004, 10: 113-118. 10.1016/j.molmed.2004.01.005.
Staalesen V, et al: Alternative splicing and mutation status of CHEK2 in stage III breast cancer. Oncogene. 2004, 23: 8535-8544. 10.1038/sj.onc.1207928.
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Lønning, P. TP53 and additional pathways in therapy resistance. Breast Cancer Res 7, S.32 (2005). https://doi.org/10.1186/bcr1075
- TP53 Mutation
- TP53 Gene
- Genetic Pathway