Using antagonistic pleiotropy to design a chemotherapy-induced evolutionary trap to target drug resistance in cancer

Lin, Kevin; Rutter, Justine C.; Xie, Abigail; Pardieu, Bryann; Winn, Emily T.; Bello, Reinaldo Dal; Forget, Antoine; Itzykson, Raphaël; Ahn, Yeong-ran; Dai, Ziwei; Sobhan, Raiyan T.; Anderson, Grace R.; Singleton, Katherine R.; Decker, Amy E.; Winter, Peter; Locasale, Jason W.; Crawford, Lorin; Puissant, Alexandre; Wood, Kris C.

doi:10.1038/s41588-020-0590-9

Cited by 54 publications

(47 citation statements)

References 68 publications

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“…5a). It follows that the order of drug administration greatly influences the treatment effects in the sequential treatment method, which is consistent with recent studies 43,44 . We also illustrate the tumor response when treated with the two drugs simultaneously (see the pentagons in Fig.…”

Section: Resultssupporting

confidence: 90%

A mathematical model for phenotypic heterogeneity in breast cancer with implications for therapeutic strategies

Thirumalai

2021

Preprint

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Inevitably, almost all cancer patients develop resistance to targeted therapy. Intratu- mor heterogeneity (ITH), which refers to coexistence of distinct clones within a single tumor, is a major cause of drug resistance. Mathematical models that explain exper- iments quantitatively is useful in understanding the origin of ITH, which then could be used to explore scenarios for efficacious therapy. Here, we develop a mathematical model to investigate ITH in breast cancer by exploiting the observation that HER2+ and HER2- cells could divide symmetrically (producing two identical daughter cells) or asymmetrically (HER2+ produces one HER2+ and one HER2- cell, for example). Our predictions for the evolution of cell fractions of HER2+ and HER2- cells are in quantitative agreement with single-cell experiments. Remarkably, the colony size of HER2+ cells emerging from a single HER2- cell (or vice versa), which occurs in about four cell doublings, agrees perfectly with experimental results, without tweaking any parameter in the model. The theory also quantitatively explains experimental data on the responses of breast cancer tumor under different treatment protocols. We then used the model to predict that, not only the order of two drugs, but also the treatment period for each drug and also the tumor cell plasticity could be manipulated to improve the treatment efficacy. Mathematical models, when integrated with data on patients, make possible exploration of a broad range of parameters readily, which might provide insights in devising effective therapies.

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Section: Resultssupporting

confidence: 90%

A mathematical model for phenotypic heterogeneity in breast cancer with implications for therapeutic strategies

Thirumalai

2021

Preprint

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“…MYC showed no changes or mild augmentation at most in spite of a marked increase in mRNA. Together, these data highlight both transcriptional and post-transcriptional regulation of MYC/MYCN by BETi in EPN, as previously reported in acute myeloid leukemia [ 54 ]. In addition, because of the overall modest modulation of these transcription factors, very likely they are not the main BET targets in EPN.…”

Section: Discussionsupporting

confidence: 85%

The BET Inhibitor OTX015 Exhibits In Vitro and In Vivo Antitumor Activity in Pediatric Ependymoma Stem Cell Models

Servidei

Meco

Martini

et al. 2021

IJMS

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Childhood ependymomas are heterogenous chemoresistant neoplasms arising from aberrant stem-like cells. Epigenome deregulation plays a pivotal role in ependymoma pathogenesis, suggesting that epigenetic modifiers hold therapeutic promise against this disease. Bromodomain and extraterminal domain (BET) proteins are epigenome readers of acetylated signals in histones and coactivators for oncogenic and stemness-related transcriptional networks, including MYC/MYCN (Proto-Oncogene, BHLH Transcritpion Factor)-regulated genes. We explored BET inhibition as an anticancer strategy in a panel of pediatric patient-derived ependymoma stem cell models by OTX015-mediated suppression of BET/acetylated histone binding. We found that ependymoma tissues and lines express BET proteins and their targets MYC and MYCN. In vitro, OTX015 reduced cell proliferation by inducing G0/G1-phase accumulation and apoptosis at clinically tolerable doses. Mechanistically, inhibitory p21 and p27 increased in a p53-independent manner, whereas the proliferative driver, phospho-signal transducer and activator of transcription 3 (STAT3), decreased. Upregulation of apoptosis-related proteins and survivin downregulation were correlated with cell line drug sensitivity. Minor alterations of MYC/MYCN expression were reported. In vivo, OTX015 significantly improved survival in 2/3 orthotopic ependymoma models. BET proteins represent promising targets for pharmaceutical intervention with OTX015 against ependymoma. The identification of predictive determinants of sensitivity may help identify ependymoma molecular subsets more likely to benefit from BET inhibitor therapies.

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“…A growing body of evidence recognizes emergence of "collateral sensitivities", or increased susceptibility to a second therapy as a fitness trade-off in cancer cells following the development of resistance to initial treatment or other perturbations [57][58][59] . This raises a possibility of rationally constructing synthetic lethalitybased treatment approaches exploiting such antagonistic pleiotropic mechanisms 60,61 . The concept that the same genetic defect may be protective in the context of a specific type of DNA damage yet make cells vulnerable to a different type of genotoxic insult has been described 62 .…”

Section: Discussionmentioning

confidence: 99%

DNMT3A harboring leukemia-associated mutations directs sensitivity to DNA damage at replication forks

Venugopal

Nowialis

Feng

et al. 2021

Preprint

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Mutations in the DNA methyltransferase 3A (DNMT3A) gene are recurrent in de novo acute myeloid leukemia (AML) and are associated with resistance to standard chemotherapy, disease relapse, and poor prognosis, especially in advanced-age patients. Previous gene expression studies in cells with DNMT3A mutations identified deregulation of cell cycle-related signatures implicated in DNA damage response and replication fork integrity, suggesting sensitivity to replication stress. Here we tested whether pharmacologically-induced replication fork stalling creates a therapeutic vulnerability in cells with DNMT3A(R882) mutations. We observed increased sensitivity to nucleoside analogs such as cytarabine in multiple cellular systems expressing mutant DNMT3A, ectopically or endogenously, in vitro and in vivo. Analysis of DNA damage signaling in response to cytarabine revealed persistent intra-S phase checkpoint activation, accompanied by accumulation of DNA damage in the DNMT3A(R882) overexpressing cells, which was only partially resolved after drug removal and carried through mitosis, resulting in micronucleation. Pulse-chase double-labeling experiments with EdU and BrdU after cytarabine wash-out demonstrated that cells with DNMT3A(mut) were able to restart replication but showed a higher rate of fork collapse. Gene expression profiling by RNA-seq identified deregulation of pathways associated with cell cycle progression and p53 activation, as well as metabolism and chromatin. Together, our studies show that cells with DNMT3A mutations have a defect in recovery from replication fork arrest and subsequent accumulation of unresolved DNA damage, which may have therapeutic tractability. These results demonstrate that, in addition to its role in epigenetic control, DNMT3A contributes to preserving genome integrity during DNA replication.

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Using antagonistic pleiotropy to design a chemotherapy-induced evolutionary trap to target drug resistance in cancer

Cited by 54 publications

References 68 publications

A mathematical model for phenotypic heterogeneity in breast cancer with implications for therapeutic strategies

A mathematical model for phenotypic heterogeneity in breast cancer with implications for therapeutic strategies

The BET Inhibitor OTX015 Exhibits In Vitro and In Vivo Antitumor Activity in Pediatric Ependymoma Stem Cell Models

DNMT3A harboring leukemia-associated mutations directs sensitivity to DNA damage at replication forks

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