Restoring p53 in cancer: the promises and the challenges

摘要

This perspective was written in celebration of Dr Arnold J. Levine’s 80th birthday. I chose to write this prospective about restoration of p53 activity in tumors for two reasons: Arnie (as we all know him) has become interested in restoring p53 activity in tumor cells and such a review did not exist. Arnie was also my postdoctoral advisor and writing this perspective is just a small tribute for the huge impact he has had on my research career (and that of many others), from supporting me when I left his laboratory for a faculty position before I had even published a paper, to serving as a sounding board for numerous ideas. Arnie is an amazing thinker. He is able to almost effortlessly incorporate new knowledge into current thinking and collate a big picture. It has been my pleasure to interact with him scientifically on numerous occasions. I want to thank Arnie from the bottom of my heart for sharing with me his love of science, his critical thinking skills, and his friendship. p53 pathway inactivation The p53 tumor suppressor is inactivated in most (and possibly all) cancers via various mechanisms indicating a potent role in inhibiting tumor cell growth (). The idea of restoring wild-type p53 function in tumors has gained traction and is likely feasible in some tumors. However, since the pathway is inactivated by deletion or mutation of p53 or by overexpression of its inhibitors Mdm2 and Mdm4, amongst other mechanisms, p53 reactivation will have to be uniquely tailored to the genetics of a specific tumor type. For example, tumors with elevated levels of the p53 inhibitors Mdm2 or Mdm4, which retain a wild-type p53 gene, should be treated with drugs that disrupt binding of these inhibitors to p53 to restore p53 function. Tumors lacking p53, on the other hand, need to reintroduce p53 through a virus encoding wild-type p53 or convert mutant p53 to wild type. Genetically modified mouse models have been used to examine p53 restoration in various contexts and will be reviewed here. Tumor responses have been heterogeneous suggesting that other factors contribute to the outcome. Resistance mechanisms will also likely emerge and need to be understood in more detail. Restoring p53 in tumors lacking p53 Initial p53 reactivation studies in mouse models employed p53 alleles that were not functional but could be reactivated in a Cre-dependent manner. The Jacks laboratory generated a wild-type p53 locus with a lox-stop-lox (LSL) cassette in the first intron effectively eliminating p53 expression but allowing p53 re-expression in the presence of Cre recombinase (). They also generated a Cre-ERsupT2/sup mouse in which the Cre recombinase is active only in the presence of Tamoxifen. Similar to germline p53sup?/?/sup mice, the LSL-p53 homozygous mice with the Cre-ERsupT2/sup allele develop autochthonous lymphomas and sarcomas due to loss of p53 function. Tamoxifen injections allow tumors to re-express p53 and thus can be used to study p53 restoration. A total of 70% (7/10) of these tumors regressed and 20% showed tumor stasis (1 T-cell lymphoma and 1 osteosarcoma). One tumor lost the Cre-ERsupT2/sup allele and thus grew like controls. In this context, p53 restoration led to apoptosis in lymphomas but decreased proliferation, cell cycle arrest, and senescence in sarcomas (). In these experiments, all tumors with restoration of wild-type p53 responded albeit to varying depth. Table 1 p53 restoration models. Genotype p53 loss/restoration Tumors Effects on tumor growth Cellular response Reference p53supLSL/LSL/sup ; Cre-ERsupT2/sup Germline Lymphomas Regression Apoptosis Sarcomas Regression; stasis Cell cycle arrest; senescence p53supNeo/?/sup ; CAG-CreER Germline Lymphomas Regression Apoptosis Angiosarcomas Regression Senescence p53supNeo/R172H/sup ; CAG-CreER Germline Lymphomas Stasis Apoptosis; senescence Angiosarcomas Stasis Senescence; decreased cell proliferation p53supNeo/R172H/sup ; Cre-ERsupT2/sup Germline Lymphomas Mixed Apoptosis HaRassupV12/sup ; p53 shRNA Carcinoma only Hepatocellular carcinomas Regression Senescence; immune response Eμ-myc ; p53ERsupTAM/+/sup B-cells B-cell lymphomas Delay Apoptosis Mdm2Tg ; p53supNeo/Neo/sup ; CAG-CreER Germline Angiosarcomas Stasis Decreased proliferation; senescence Genotype p53 loss/restoration Tumors Effects on tumor growth Cellular response Reference p53supLSL/LSL/sup ; Cre-ERsupT2/sup Germline Lymphomas Regression Apoptosis Sarcomas Regression; stasis Cell cycle arrest; senescence p53supNeo/?/sup ; CAG-CreER Germline Lymphomas Regression Apoptosis Angiosarcomas Regression Senescence p53supNeo/R172H/sup ; CAG-CreER Germline Lymphomas Stasis Apoptosis; senescence Angiosarcomas Stasis Senescence; decreased cel