How do real tumors become resistant to cisplatin?

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Abstract
Lab research on cultured tumor cells selected for resistance to platinum compounds has turned up a diverse array of resistance mechanisms. In contrast, we recently found that mouse mammary tumors containing irrepairable null alleles of the Brca1 gene do not become resistant to cisplatin ever, although they invariably become resistant to a variety of other anti-cancer drugs. Each new treatment with cisplatin shrinks the tumor to a very small remnant, but relapse always occurs. The BRCA1 missing in these mouse tumors is essential for the homology-directed DNA repair (HR) that allows error-free repair of the duplex breaks caused by the excision of platin-DNA adducts. The mouse tumor results therefore raise the question whether the cisplatin resistance mechanisms identified in vitro can actually overcome an irreversible defect in DNA repair in real tumors. This question is underlined by recent analyses of tumor samples of patients with ovarian cancer that have uncovered a new platin resistance mechanism: thes...