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Drug Resistance and the Tumor Suppressor p53: The Paradox of Wild-Type Genotype in Chemorefractory Cancers

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Drug Resistance in Cancer Cells

Abstract

The tumor suppressor p53 has a central role in drug-induced cell death. Its mutation in about 50% of all cancers is a source of drug resistance from the loss in apoptotic signaling, but loss of apoptosis is also found in many resistant tumors that retain wild-type p53 and this represents a paradox. Indeed, resistance seems to be substantially greater with wild-type p53 present as compared to mutant p53. From the perspective of response and survival in cancer patients, responses are observed independent of p53 gene status, but the 5-year survival rate is significantly greater when wild-type p53 is present. This indicates that an effort to increase the response rate in cancers having the wild-type p53 should translate into an increase in the survival rate. To accomplish this goal, an understanding of the mechanisms contributing to resistance in wild-type p53 cancers becomes important. These mechanisms are multifactorial and include loss in DNA damage recognition, alterations in post-translational modification of p53, failure to activate p53 due to target gene silencing, and failure to transrepress antiapoptotic genes.

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Acknowledgments

Supported by NIH Grant RO1 CA127263.

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  1. Department of Experimental Therapeutics, Box 353, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA

    Zahid H. Siddik

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    Siddik, Z.H. (2009). Drug Resistance and the Tumor Suppressor p53: The Paradox of Wild-Type Genotype in Chemorefractory Cancers. In: Siddik, Z., Mehta, K. (eds) Drug Resistance in Cancer Cells. Springer, New York, NY. https://doi.org/10.1007/978-0-387-89445-4_9

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