A targeted treatment with off-target risks

Fruman, David A.; O’Brien, Susan

doi:10.1038/nature21504

Cited by 18 publications

(14 citation statements)

References 12 publications

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“…While APOBEC3B plays a prominent role in cancer mutagenesis, several other AID/APOBEC family members also have mutagenic roles and affect DNA integrity [ 9 , 14 ]. Most of them have separate distinct specificities for genome sequence context [ 2 , 8 – 10 , 15 , 16 ]. However, a possible overlap between the activities of APOBEC3B and APOBEC3A has not been fully resolved.…”

Section: Introductionmentioning

confidence: 99%

Correlation of gene expression and associated mutation profiles of APOBEC3A, APOBEC3B, REV1, UNG, and FHIT with chemosensitivity of cancer cell lines to drug treatment

2018

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BackgroundThe APOBEC gene family of cytidine deaminases plays important roles in DNA repair and mRNA editing. In many cancers, APOBEC3B increases the mutation load, generating clusters of closely spaced, single-strand-specific DNA substitutions with a characteristic hypermutation signature. Some studies also suggested a possible involvement of APOBEC3A, REV1, UNG, and FHIT in molecular processes affecting APOBEC mutagenesis. It is important to understand how mutagenic processes linked to the activity of these genes may affect sensitivity of cancer cells to treatment.ResultsWe used information from the Cancer Cell Line Encyclopedia and the Genomics of Drug Sensitivity in Cancer resources to examine associations of the prevalence of APOBEC-like motifs and mutational loads with expression of APOBEC3A, APOBEC3B, REV1, UNG, and FHIT and with cell line chemosensitivity to 255 antitumor drugs. Among the five genes, APOBEC3B expression levels were bimodally distributed, whereas expression of APOBEC3A, REV1, UNG, and FHIT was unimodally distributed. The majority of the cell lines had low levels of APOBEC3A expression. The strongest correlations of gene expression levels with mutational loads or with measures of prevalence of APOBEC-like motif counts and kataegis clusters were observed for REV1, UNG, and APOBEC3A. Sensitivity or resistance of cell lines to JQ1, palbociclib, bicalutamide, 17-AAG, TAE684, MEK inhibitors refametinib, PD-0325901, and trametinib and a number of other agents was correlated with candidate gene expression levels or with abundance of APOBEC-like motif clusters in specific cancers or across cancer types.ConclusionsWe observed correlations of expression levels of the five candidate genes in cell line models with sensitivity to cancer drug treatment. We also noted suggestive correlations between measures of abundance of APOBEC-like sequence motifs with drug sensitivity in small samples of cell lines from individual cancer categories, which require further validation in larger datasets. Molecular mechanisms underlying the links between the activities of the products of each of the five genes, the resulting mutagenic processes, and sensitivity to each category of antitumor agents require further investigation.

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Section: Introductionmentioning

confidence: 99%

Correlation of gene expression and associated mutation profiles of APOBEC3A, APOBEC3B, REV1, UNG, and FHIT with chemosensitivity of cancer cell lines to drug treatment

2018

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“…Despite over 100 y of study (6), the cell/cancer type-selective toxicities exhibited by drugs that interfere with DNA metabolism remain poorly understood. A correlation between rapid neoplasm proliferation and sensitivity toward DNA synthesis inhibition is often mentioned (7), but this hypothesis would not predict that slowproliferating "indolent" cancers can be cured with DNA synthesis inhibitors (8), nor does it explain how healthy animals can efficiently anabolize these compounds yet exhibit high resistance toward their effects in vivo (9). Cytarabine (ara-C), gemcitabine, cladribine, and fludarabine are widely used nucleoside prodrugs that can be phosphorylated and incorporated into nucleic acids in vivo, potentially causing chain termination and cell death (10,11).…”

mentioning

confidence: 99%

Superresolution imaging of individual replication forks reveals unexpected prodrug resistance mechanism

Triemer

Messikommer

Glasauer

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Many drugs require extensive metabolism en route to their targets. High-resolution visualization of prodrug metabolism should therefore utilize analogs containing a small modification that does not interfere with its metabolism or mode of action. In addition to serving as mechanistic probes, such analogs provide candidates for theranostics when applied in both therapeutic and diagnostic modalities. Here a traceable mimic of the widely used anticancer prodrug cytarabine (ara-C) was generated by converting a single hydroxyl group to azide, giving "AzC." This compound exhibited the same biological profile as ara-C in cell cultures and zebrafish larvae. Using azide-alkyne "click" reactions, we uncovered an apparent contradiction: drug-resistant cells incorporated relatively large quantities of AzC into their genomes and entered S-phase arrest, whereas drug-sensitive cells incorporated only small quantities of AzC. Fluorescence microscopy was used to elucidate structural features associated with drug resistance by characterizing the architectures of stalled DNA replication foci containing AzC, EdU, γH2AX, and proliferating cell nuclear antigen (PCNA). Three-color superresolution imaging revealed replication foci containing one, two, or three partially resolved replication forks. Upon removing AzC from the media, resumption of DNA synthesis and completion of the cell cycle occurred before complete removal of AzC from genomes in vitro and in vivo. These results revealed an important mechanism for the low toxicity of ara-C toward normal tissues and drug-resistant cancer cells, where its efficient incorporation into DNA gives rise to highly stable, stalled replication forks that limit further incorporation of the drug, yet allow for the resumption of DNA synthesis and cellular division following treatment.

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“…2,38,39 Moreover, administration of PI3Ka inhibitors in the clinic for the treatment of cancer is frequently associated with insulin resistance, hyperglycemia, and hyperinsulinemia. 40 Although animals at the highest dose in the 3-month toxicology study were often in poor health, there was no evidence of dysfunctional glucose homeostasis, such as elevated glucose levels. Although all class 1 PI3K isoforms are expressed in platelets, the kinase activity of PI3Kb isoform plays a critical role in regulating platelet responses initiated by several platelet receptors, particularly at high shear stress during arterial thrombosis.…”

Section: Discussionmentioning

confidence: 94%

Phosphatidylinositol 3-Kinase δ Inhibitor-Induced Immunomodulation and Secondary Opportunistic Infection in the Cynomolgus Monkey (Macaca fascicularis)

et al. 2020

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Phosphatidylinositol 3-kinases (PI3Ks) regulate intracellular signaling events for multiple cell surface receptors. Phosphatidylinositol 3-kinase δ, 1 of 4 class I PI3K isoforms, is primarily found in leukocytes and regulates immune cell functions. Here, we report changes in the immune and digestive systems that were associated with AMG2519493, a highly selective small-molecule PI3Kδ inhibitor. Following 1- or 3-month oral repeat dosing in the cynomolgus monkey, changes were observed in circulating B cells, lymphoid tissues (spleen, lymph nodes, gut-associated lymphoid tissue, tonsil), and the digestive tract. Decreased circulating B cells and lymphoid cellularity in B cell-rich zones in lymphoid tissues were attributed to the intended pharmacologic activity of AMG2519493. Dose- and duration-dependent digestive system toxicity was characterized by inflammation in the large intestine and secondary opportunistic infections restricted to the digestive tract. Digestive tract changes were associated with moribundity and mortality at high-dose levels, and the effect level decreased with increased duration of exposure. These observations demonstrate the role of PI3Kδ in regulation of the immune system and of host resistance to opportunistic infections of the digestive tract.

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A targeted treatment with off-target risks

Cited by 18 publications

References 12 publications

Correlation of gene expression and associated mutation profiles of APOBEC3A, APOBEC3B, REV1, UNG, and FHIT with chemosensitivity of cancer cell lines to drug treatment

Correlation of gene expression and associated mutation profiles of APOBEC3A, APOBEC3B, REV1, UNG, and FHIT with chemosensitivity of cancer cell lines to drug treatment

Superresolution imaging of individual replication forks reveals unexpected prodrug resistance mechanism

Phosphatidylinositol 3-Kinase δ Inhibitor-Induced Immunomodulation and Secondary Opportunistic Infection in the Cynomolgus Monkey (Macaca fascicularis)

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