Predicting and Overcoming Taxane Chemoresistance

Rodrigues-Ferreira, Sylvie; Moindjie, Hadia; Haykal, Maria M.; Nahmias, Clara

doi:10.1016/j.molmed.2020.09.007

Cited by 16 publications

(8 citation statements)

References 100 publications

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“…Microtubules-targeting agents, which disrupt microtubule dynamics and block mitotic progression, are the most important antimitotic drugs used in the clinical treatment of both solid tumors and hematological malignancies [4,5]. However, the clinical utility of microtubules-targeting agents is limited due to severe adverse effects and drug resistance [6]. Recently, inhibitors of mitotic kinase have emerged as efficacious alternative treatment options for patients with solid tumors.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Polo-like kinase 4 induces mitotic defects and DNA damage in diffuse large B-cell lymphoma

et al. 2021

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Polo-like kinase 4 (PLK4), a key regulator of centriole biogenesis, has recently been shown to play key roles in tumorigenesis. Blocking PLK4 expression by interference or targeted drugs exhibits attractive potential in improving the efficacy of chemotherapy. Nevertheless, the role of PLK4 in diffuse large B-cell lymphoma (DLBCL) is still undefined. In this study, we discover that PLK4 is a potential target for the treatment of DLBCL, and demonstrate the efficacy of a PLK4 inhibitor when used in combination with doxorubicin. Pharmaceutical inhibition of PLK4 with CFI-400945 inhibited DLBCL cell proliferation and induced apoptotic cell death. The anti-tumor effects were accompanied by mitotic defects, including polyploidy and cytokinesis failure. Activation of p53 and Hippo/YAP tumor suppressor signaling pathway was identified as the potential mechanisms driving CFI-400945 activity. Moreover, CFI-400945 treatment resulted in activation of DNA damage response. Combining CFI-400945 with doxorubicin markedly delayed tumor progression in DLBCL xenografts. Finally, PLK4 was increased in primary DLBCL tissues and cell lines. High levels of PLK4 expression were associated with poor survival in the patients receiving CHOP-based treatment, implicating PLK4 as a predictive biomarker of DLBCL chemosensitivity. These results provide the therapeutic potential of CFI-400945 both as monotherapy or in combination with doxorubicin for the treatment of DLBCL.

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Section: Introductionmentioning

confidence: 99%

Inhibition of Polo-like kinase 4 induces mitotic defects and DNA damage in diffuse large B-cell lymphoma

et al. 2021

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“…Taxol resistance represents an important clinical challenge [42]. To determine whether the peptides act in this context, we selected Taxol-resistant T98G cells by exposure to increasing concentrations of the drug (Supplementary Figure S5B) and then compared them with non-selected cells for responses to Bpep and Dpep.…”

Section: Bpep and Dpep Act In Combination With Other Cancer Therapeuticsmentioning

confidence: 99%

Cell-Penetrating CEBPB and CEBPD Leucine Zipper Decoys as Broadly Acting Anti-Cancer Agents

Zhou

Sun

Pasquier

et al. 2021

Cancers

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Transcription factors are key players underlying cancer formation, growth, survival, metastasis and treatment resistance, yet few drugs exist to directly target them. Here, we characterized the in vitro and in vivo anti-cancer efficacy of novel synthetic cell-penetrating peptides (Bpep and Dpep) designed to interfere with the formation of active leucine-zipper-based dimers by CEBPB and CEBPD, transcription factors implicated in multiple malignancies. Both peptides similarly promoted apoptosis of multiple tumor lines of varying origins, without such effects on non-transformed cells. Combined with other treatments (radiation, Taxol, chloroquine, doxorubicin), the peptides acted additively to synergistically and were fully active on Taxol-resistant cells. The peptides suppressed expression of known direct CEBPB/CEBPD targets IL6, IL8 and asparagine synthetase (ASNS), supporting their inhibition of transcriptional activation. Mechanisms by which the peptides trigger apoptosis included depletion of pro-survival survivin and a required elevation of pro-apoptotic BMF. Bpep and Dpep significantly slowed tumor growth in mouse models without evident side effects. Dpep significantly prolonged survival in xenograft models. These findings indicate the efficacy and potential of Bpep and Dpep as novel agents to treat a variety of cancers as mono- or combination therapies.

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“…It is therefore of utmost importance to identify biomarkers able to select with high confidence the patients who are at high risk to resist to chemotherapy. These predictive biomarkers represent a necessary step towards therapeutic de-escalation and future design of new targeted strategies for chemoresistant breast tumors [ 76 ].…”

Section: Atip3 Is a Predictive Biomarker Of Taxane-based Chemotherapy In Breast Cancermentioning

confidence: 99%

Microtubule-Associated Protein ATIP3, an Emerging Target for Personalized Medicine in Breast Cancer

Haykal

Rodrigues-Ferreira

Nahmias

2021

Cells

Self Cite

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Breast cancer is the leading cause of death by malignancy among women worldwide. Clinical data and molecular characteristics of breast tumors are essential to guide clinician’s therapeutic decisions. In the new era of precision medicine, that aims at personalizing the treatment for each patient, there is urgent need to identify robust companion biomarkers for new targeted therapies. This review focuses on ATIP3, a potent anti-cancer protein encoded by candidate tumor suppressor gene MTUS1, whose expression levels are markedly down-regulated in breast cancer. ATIP3 is a microtubule-associated protein identified both as a prognostic biomarker of patient survival and a predictive biomarker of breast tumors response to taxane-based chemotherapy. We present here recent studies pointing out ATIP3 as an emerging anti-cancer protein and a potential companion biomarker to be combined with future personalized therapy against ATIP3-deficient breast cancer.

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Predicting and Overcoming Taxane Chemoresistance

Cited by 16 publications

References 100 publications

Inhibition of Polo-like kinase 4 induces mitotic defects and DNA damage in diffuse large B-cell lymphoma

Inhibition of Polo-like kinase 4 induces mitotic defects and DNA damage in diffuse large B-cell lymphoma

Cell-Penetrating CEBPB and CEBPD Leucine Zipper Decoys as Broadly Acting Anti-Cancer Agents

Microtubule-Associated Protein ATIP3, an Emerging Target for Personalized Medicine in Breast Cancer

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