Abstract
Aim:Resistance to fluoropyrimidine drugs (FPs) is a major cause of mortality in colorectal cancer (CRC). We assessed the potency advantage of the polymeric FP F10 relative to 5-fluorouracil (5FU) in four human CRC cell lines that differ only in TP53 mutational status to determine how p53 mutations affect drug response and whether F10 is likely to improve outcomes.Methods:HCT-116 human CRC cells (p53+/+) and three isogenic variants (p53−/−, R248W/+, R248W/−) were assessed for drug response. Resistance factors were derived from cell viability data and used to establish the relative potency advantage for F10. Rescue studies with exogenous uridine/thymidine determined if cytotoxicity resulted from DNA-directed processes.Results:Significant resistance to 5-FU resulted from p53-loss or from gain-of-function (GOF) mutation (R248W) and was greatest when GOF mutation was coupled with loss of wild-type p53. F10 is much more potent than 5-FU (137–314-fold depending on TP53 mutational status). F10 and 5-FU induce apoptosis by DNA- and RNA-directed mechanisms, respectively, and only F10 shows a modest enhancement in cytotoxicity upon co-treatment with leucovorin.Conclusion:TP53 mutational status affects inherent sensitivity to FPs, with p53 GOF mutations most deleterious. F10 is much more effective than 5-FU regardless of TP53 mutations and has potential to be effective to CRC that is resistant to 5-FU due, in part, to TP53 mutations.6,7
Highlights
Colorectal cancer (CRC) is the 3rd leading cause of cancer-related deaths among both men and women
While TP53 status is important for response of GI-tract and CRC cells to 5-FU, investigations to test whether TP53 status predicts therapy response in CRC have yielded conflicting results[8,15], possibly due to different methods being used to assess TP53 mutational status[16]
While further clinical investigation is required to assess whether TP53 mutational status should be used to direct therapy decisions in CRC based on 5-FU response, it is important to establish that candidates for replacing 5-FU demonstrate strong activity towards CRC with p53 mutations since this constitutes 40%-50% of CRC cases
Summary
Colorectal cancer (CRC) is the 3rd leading cause of cancer-related deaths among both men and women. Factors responsible for disease recurrence in CRC patients treated with 5-FU remain incompletely characterized, growing evidence implicates TP53 mutations, which occur in up to half of CRC cases, as an important risk factor[5,6,7,8]. While TP53 status is important for response of GI-tract and CRC cells to 5-FU, investigations to test whether TP53 status predicts therapy response in CRC have yielded conflicting results[8,15], possibly due to different methods being used to assess TP53 mutational status[16]. While further clinical investigation is required to assess whether TP53 mutational status should be used to direct therapy decisions in CRC based on 5-FU response, it is important to establish that candidates for replacing 5-FU demonstrate strong activity towards CRC with p53 mutations since this constitutes 40%-50% of CRC cases
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