A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage

Ladds, Marcus J.G.W.; Leeuwen, Ingeborg M.M. van; Drummond, Catherine J.; Chu, Su; Healy, Alan R.; Popova, Gergana; Fernández, Andrés Pastor; Mollick, Tanzina; Darekar, Suhas; Sedimbi, Saikiran K.; Nekulova, Marta; Sachweh, Marijke C.C.; Campbell, Johanna; Higgins, Maureen; Tuck, Chloe; Popa, Mihaela; Safont, Mireia Mayoral; Gélébart, Pascal; Fandalyuk, Zinayida; Thompson, Alastair; Svensson, Richard; Gustavsson, Anna‐Lena; Johansson, Lars; Färnegårdh, Katarina; Yngve, Ulrika; Saleh, Aljona; Haraldsson, Martin; D’Hollander, Agathe C. A.; Franco, Marcela; Zhao, Yan; Håkansson, Maria; Walse, Björn; Larsson, Karin; Peat, Emma M.; Pelechano, Vicent; Lunec, John; Vojtěšek, Bořivoj; Carmena, Mar; Earnshaw, William C.; McCarthy, Anna R.; Westwood, Nicholas J.; Arsenian-Henriksson, Marie; Lane, David P.; Bhatia, Ravi; McCormack, Emmet; Laı́n, Sonia

doi:10.1038/s41467-018-03441-3

Cited by 73 publications

(103 citation statements)

References 36 publications

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“…The lack of balanced dNTP pool can induce delay of replication fork progression and DNA replication as well as inhibition of RNA synthesis and proper assembly of ribosome 35,36 . In accordance with previous reports 5,7,37,38 , we have observed cell cycle arrest in the early S phase after inhibition of DHODH activity by leflunomide, a clinically used agent in patients with rheumatoid arthritis and multiple sclerosis 39,40 . Surprisingly, we did not observe an increase in DNA damage, unlike reported previously 41 .…”

Section: Discussionsupporting

confidence: 93%

Replication and ribosomal stress induced by targeting pyrimidine synthesis and cellular checkpoints suppress p53-deficient tumors

et al. 2020

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p53-mutated tumors often exhibit increased resistance to standard chemotherapy and enhanced metastatic potential. Here we demonstrate that inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme of the de novo pyrimidine synthesis pathway, effectively decreases proliferation of cancer cells via induction of replication and ribosomal stress in a p53-and checkpoint kinase 1 (Chk1)-dependent manner. Mechanistically, a block in replication and ribosomal biogenesis result in p53 activation paralleled by accumulation of replication forks that activate the ataxia telangiectasia and Rad3-related kinase/Chk1 pathway, both of which lead to cell cycle arrest. Since in the absence of functional p53 the cell cycle arrest fully depends on Chk1, combined DHODH/Chk1 inhibition in p53dysfunctional cancer cells induces aberrant cell cycle re-entry and erroneous mitosis, resulting in massive cell death. Combined DHODH/Chk1 inhibition effectively suppresses p53-mutated tumors and their metastasis, and therefore presents a promising therapeutic strategy for p53-mutated cancers.

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Section: Discussionsupporting

confidence: 93%

Replication and ribosomal stress induced by targeting pyrimidine synthesis and cellular checkpoints suppress p53-deficient tumors

et al. 2020

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“…Oncogenic mutations in JAK2 (HEL), TET2 (HEL and SKM-1), ASXL1 (NOMO-1, SKM-1, and TF-1) and FLT3 (MOLM-13 and MV4-11) are also represented. Because upregulation of p53 has been proposed as a mechanism of anti-tumor activity by DHODH inhibition [12], we assessed whether TP53 mutation status affects the IC 50 of BAY 2402234 in AML cell lines. We did not identify any correlation between sensitivity to BAY 2402234 and the TP53 mutation status of the AML cell lines.…”

Section: Bay 2402234 Induces Differentiation and Inhibits Proliferatimentioning

confidence: 99%

The novel dihydroorotate dehydrogenase (DHODH) inhibitor BAY 2402234 triggers differentiation and is effective in the treatment of myeloid malignancies

et al. 2019

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Acute myeloid leukemia (AML) is a devastating disease, with the majority of patients dying within a year of diagnosis. For patients with relapsed/refractory AML, the prognosis is particularly poor with currently available treatments. Although genetically heterogeneous, AML subtypes share a common differentiation arrest at hematopoietic progenitor stages. Overcoming this differentiation arrest has the potential to improve the long-term survival of patients, as is the case in acute promyelocytic leukemia (APL), which is characterized by a chromosomal translocation involving the retinoic acid receptor alpha gene. Treatment of APL with all-trans retinoic acid (ATRA) induces terminal differentiation and apoptosis of leukemic promyelocytes, resulting in cure rates of over 80%. Unfortunately, similarly efficacious differentiation therapies have, to date, been lacking outside of APL. Inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo pyrimidine synthesis pathway, was recently reported to induce differentiation of diverse AML subtypes. In this report we describe the discovery and characterization of BAY 2402234-a novel, potent, selective and orally bioavailable DHODH inhibitor that shows monotherapy efficacy and differentiation induction across multiple AML subtypes. Herein, we present the preclinical data that led to initiation of a phase I evaluation of this inhibitor in myeloid malignancies.

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“…DHODH has also been investigated for a role in cancer, including melanoma (58) and acute myeloid leukemia (59), and decreased expression of DHODH was associated with breast cancer risk (60). Several other studies have examined the utility of DHODH inhibitors in cancer by inducing cell-cycle arrest and apoptosis in cancer cells (59,(61)(62)(63)(64)(65)(66). Although DHODH has not been previously associated with lung cancer risk, the abundance of biological evidence for its pleiotropic role in cancer gives credibility to the association.…”

Section: Discussionmentioning

confidence: 99%

Cross-Cancer Pleiotropic Associations with Lung Cancer Risk in African Americans

Jones

Bradford

Amos

et al. 2019

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Identifying genetic variants with pleiotropic associations across multiple cancers can reveal shared biologic pathways. Prior pleiotropic studies have primarily focused on European-descent individuals. Yet population-specific genetic variation can occur, and potential pleiotropic associations among diverse racial/ethnic populations could be missed. We examined cross-cancer pleiotropic associations with lung cancer risk in African Americans. Methods: We conducted a pleiotropic analysis among 1,410 African American lung cancer cases and 2,843 controls. We examined 36,958 variants previously associated (or in linkage disequilibrium) with cancer in prior genome-wide association studies. Logistic regression analyses were conducted, adjusting for age, sex, global ancestry, study site, and smoking status. Results: We identified three novel genomic regions significantly associated (FDR-corrected P <0.10) with lung cancer risk (rs336958 on 5q14.3, rs7186207 on 16q22.2, and rs11658063 on 17q12). On chromosome16q22.2, rs7186207 was significantly associated with reduced risk [OR ¼ 0.43; 95% confidence interval (CI), 0.73-0.89], and functional annotation using GTEx showed rs7186207 modifies DHODH gene expression. The minor allele at rs336958 on 5q14.3 was associated with increased lung cancer risk (OR ¼ 1.47; 95% CI, 1.22-1.78), whereas the minor allele at rs11658063 on 17q12 was associated with reduced risk (OR ¼ 0.80; 95% CI, 0.72-0.90). Conclusions: We identified novel associations on chromosomes 5q14.3, 16q22.2, and 17q12, which contain HNF1B, DHODH, and HAPLN1 genes, respectively. SNPs within these regions have been previously associated with multiple cancers. This is the first study to examine cross-cancer pleiotropic associations for lung cancer in African Americans. Impact: Our findings demonstrate novel cross-cancer pleiotropic associations with lung cancer risk in African Americans.

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A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage

Cited by 73 publications

References 36 publications

Replication and ribosomal stress induced by targeting pyrimidine synthesis and cellular checkpoints suppress p53-deficient tumors

Replication and ribosomal stress induced by targeting pyrimidine synthesis and cellular checkpoints suppress p53-deficient tumors

The novel dihydroorotate dehydrogenase (DHODH) inhibitor BAY 2402234 triggers differentiation and is effective in the treatment of myeloid malignancies

Cross-Cancer Pleiotropic Associations with Lung Cancer Risk in African Americans

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