Predictive Gene Signatures Determine Tumor Sensitivity to MDM2 Inhibition

Cancer Research
Jo IshizawaMichael Andreeff

Abstract

Early clinical trials using murine double minute 2 (MDM2) inhibitors demonstrated proof-of-concept of p53-induced apoptosis by MDM2 inhibition in cancer cells; however, not all wild-type TP53 tumors are sensitive to MDM2 inhibition. Therefore, more potent inhibitors and biomarkers predictive of tumor sensitivity are needed. The novel MDM2 inhibitor DS-3032b is 10-fold more potent than the first-generation inhibitor nutlin-3a. TP53 mutations were predictive of resistance to DS-3032b, and allele frequencies of TP53 mutations were negatively correlated with sensitivity to DS-3032b. However, sensitivity to DS-3032b of TP53 wild-type tumors varied greatly. We thus used two methods to create predictive gene signatures. First, by comparing sensitivity to MDM2 inhibition with basal mRNA expression profiles in 240 cancer cell lines, a 175-gene signature was defined and validated in patient-derived tumor xenograft models and ex vivo human acute myeloid leukemia (AML) cells. Second, an AML-specific 1,532-gene signature was defined by performing random forest analysis with cross-validation using gene expression profiles of 41 primary AML samples. The combination of TP53 mutation status with the two gene signatures provided the best positiv...Continue Reading

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Citations

Jul 17, 2019·Journal of Molecular Cell Biology·Gema SanzGalina Selivanova
Oct 7, 2019·Medicinal Research Reviews·Wei WangRuiwen Zhang
Aug 17, 2020·Nucleic Acids Research·Morgan A SammonsMartin Fischer
Jul 12, 2020·Leukemia·Marina KonoplevaMichael Andreeff
Oct 28, 2019·Nature Communications·Yasutaka HayashiToshio Kitamura
Feb 6, 2020·Cancer Discovery·Nicholas J ShortNaval Daver
Aug 4, 2020·Seminars in Cancer Biology·Michael J DuffyJohn Crown
Mar 25, 2021·Journal of Hematology & Oncology·Hongtao Liu
May 1, 2021·Cancers·Magdalena C Liebl, Thomas G Hofmann
Jul 27, 2021·Frontiers in Oncology·Xanthene MilesJulie Bolcaen

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