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TECHNOLOGY

HIGH FREQUENCY OF p53 MUTATIONS ACROSS CANCERS

TP53 mutations occur frequently across tumor types. TP53 is mutated in most human cancers and at an even higher frequency among difficult to treat cancers and in patients that fail first-line​therapies. Particularly high mutation rates occur in head and neck, ovarian, colorectal, lung and brain cancer among others.​

Mutation, Alternate frequency and CNA bar graph

HUNDREDS OF INFREQUENT MUTATIONS IN MUTATED p53

A Mutation-Specific Strategy Is Not Viable Given The High Number Of Point Mutations And Low Prevalence Of Each One.

Prevalence of individual p53 mutations visual data

REFERENCES

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Zhang, S., Carlsen, L., Hernandez-Borrero, L., Seyhan, A.A., Tian, X., and El-Deiry, W.S. Advanced Strategies for Therapeutic Targeting of Wild-Type and Mutant p53 in Cancer. Biomolecules. 2022 Apr 6;12(4):548. doi: 10.3390/biom12040548.

Zhang, S., Zhou, L., and El-Deiry, W.S. Small-Molecule NSC59984 Induces Mutant p53 Degradation through a ROS-ERK2-MDM2 Axis in Cancer Cells. Mol Cancer Res. 2022 Apr 1;20(4):622-636. doi: 10.1158/1541-7786.MCR-21-0149.

Tian, X., Zhang, S., Zhou, L., Seyhan, A.A., Hernandez-Borrero, L., Zhang, Y., and El-Deiry, W.S. Targeting the Integrated Stress Response in Cancer Therapy. Front Pharmacol. 2021 Sep 24:12:747837. doi: 10.3389/fphar.2021.747837. eCollection 2021.

Hernandez-Borrero, L., Dicker, D.T., Santiago, J., Sanders, J., Tian, X., Ahsan, N., Lev, A., Zhou, L., and El-Deiry, W.S. A subset of CB002 xanthine analogs bypass p53-signaling to restore a p53 transcriptome and target an S-phase cell cycle checkpoint in tumors with mutated-p53. Elife . 2021 Jul 29:10:e70429. doi: 10.7554/eLife.70429.

Hernández Borrero, L.J., and El-Deiry, W.S. Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting. Biochim Biophys Acta Rev Cancer. 2021 Aug;1876(1):188556.

Tian, X., Ahsan, N., Lulla, A., Lev, A., Abbosh, P., Dicker,D.T., Zhang, S., and El-Deiry, W.S. P53-independent partial restoration of the p53 pathway in tumors with mutated p53 through ATF4 transcriptional modulation by ERK1/2 and CDK9. Neoplasia. 2021 Mar;23(3):304-325. doi: 10.1016/j.neo.2021.01.004. Epub 2021 Feb 11.

Hernandez-Borrero, L.J., Zhang, S., Lulla, A., Dicker, D.T., El-Deiry, W.S. CB002, a novel p53 tumor suppressor pathway-restoring small molecule induces tumor cell death through the pro-apoptotic protein NOXA. Cell Cycle. 2018;17(5):557-567. doi: 10.1080/15384101.2017.1346762. Epub 2018 Feb 19.

El-Deiry, W.S. p21(WAF1) Mediates Cell-Cycle Inhibition, Relevant to Cancer Suppression and Therapy. Cancer Res. 2016 Sep 15;76(18):5189-91. doi: 10.1158/0008-5472.CAN-16-2055.

Prabhu, V.V., Hong, B., Allen, J.E., Zhang, S., Lulla, A.R., Dicker, D.T., El-Deiry, W.S. Small-Molecule Prodigiosin Restores p53 Tumor Suppressor Activity in Chemoresistant Colorectal Cancer Stem Cells via c-Jun-Mediated ΔNp73 Inhibition and p73 Activation. Cancer Res. 2016 Apr 1;76(7):1989-99.

Zhang, S., Zhou, L., Hong, B., van den Heuvel, A.P.J. Prabhu, V.V., Warfel, N.A., Kline, C.L.B. Dicker, D.T., Kopelovich, L., and El-Deiry, W.S. Small-Molecule NSC59984 Restores p53 Pathway Signaling and Antitumor Effects against Colorectal Cancer via p73 Activation and Degradation of Mutant p53. Cancer Res. 2015 Sep 15;75(18):3842-52.

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