Long-term cultivation using ineffective MDM2 inhibitor concentrations alters the drug sensitivity profiles of PL21 leukaemia cells
user-5f8cf7e04c775ec6fa691c92(2020)
摘要
Acquired MDM2 inhibitor resistance is commonly caused by loss-of-function TP53 mutations. In addition to the selection of TP53 -mutant cells by MDM2 inhibitors, MDM2 inhibitor-induced DNA damage may promote the formation of TP53 mutations. Here, we cultivated 12 sublines of the intrinsically MDM2 inhibitor-resistant TP53 wild-type acute myeloid leukaemia cell line PL21 for 52 passages in the presence of ineffective concentrations of the MDM2 inhibitor nutlin-3 but did not observe loss-of-function TP53 mutations. This suggests that MDM2 inhibitors select TP53 -mutant cells after mutations have occurred, but do not directly promote TP53 mutations. Unexpectedly, many sublines displayed increased sensitivity to the anti-cancer drugs cytarabine, doxorubicin, or gemcitabine. Consequently, therapies can affect the outcome of next-line treatments, even in the absence of a therapy response. This finding is conceptually novel. A better understanding of such processes will inform the design of improved therapy protocols in the future.
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关键词
Cytarabine,Leukemia,DNA damage,Doxorubicin,Cancer,Gemcitabine,Cell culture,Mdm2,Cancer research,Medicine
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