Systematic Drug Screening Identifies Tractable Targeted Combination Therapies in Triple-Negative Breast Cancer

Wali, Vikram B.; Langdon, Casey G.; Held, Matthew A.; Platt, James T.; Patwardhan, Gauri A.; Safonov, Anton; Aktaş, Bilge; Pusztai, Lajos; Stern, David F.; Hatzis, Christos

doi:10.1158/0008-5472.can-16-1901

Cited by 42 publications

(34 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Moreover, our results imply that especially MYC but potentially also the specific Bcl-xL regulating miRNAs, such as miR-203b-3p, may be harnessed as predictors of tumor cells' drug sensitivity in future. Finally, the data presented here also support the promising concept of combining inhibitors of the Bcl-2 family proteins with taxanes to improve the treatment response, which has already yielded promising results in preclinical models [14] , [18] , [43] , [44] .…”

Section: Discussionsupporting

confidence: 72%

MYC-Induced miR-203b-3p and miR-203a-3p Control Bcl-xL Expression and Paclitaxel Sensitivity in Tumor Cells

Aakko

Straume

Birkeland

et al. 2019

Translational Oncology

View full text Add to dashboard Cite

Taxanes are chemotherapeutic agents used in the treatment of solid tumors, particularly of breast, ovarian, and lung origin. However, patients show divergent therapy responses, and the molecular determinants of taxane sensitivity have remained elusive. Especially the signaling pathways that promote death of the taxane-treated cells are poorly characterized. Here we describe a novel part of a signaling route in which c-Myc enhances paclitaxel sensitivity through upregulation of miR-203b-3p and miR-203a-3p; two clustered antiapoptosis protein Bcl-xL controlling microRNAs. In vitro, the miR-203b-3p decreases the expression of Bcl-xL by direct targeting of the gene's mRNA 3’UTR. Notably, overexpression of the miR-203b-3p changed the fate of paclitaxel-treated breast and ovarian cancer cells from mitotic slippage to cell death. In breast tumors, high expression of the miR-203b-3p and MYC was associated with better therapy response and patient survival. Interestingly, in the breast tumors, MYC expression correlated negatively with BCL2L1 expression but positively with miR-203b-3p and miR-203a-3p. Finally, silencing of MYC suppressed the transcription of both miRNAs in breast tumor cells. Pending further validation, these results may assist in patient stratification for taxane therapy.

show abstract

Section: Discussionsupporting

confidence: 72%

MYC-Induced miR-203b-3p and miR-203a-3p Control Bcl-xL Expression and Paclitaxel Sensitivity in Tumor Cells

Aakko

Straume

Birkeland

et al. 2019

Translational Oncology

View full text Add to dashboard Cite

show abstract

“…The Brd4 inhibitor JQ1 suppressed iNOS expression, NO production, and cell hyper-aggressiveness much more powerfully than an inhibitor of iNOS enzymatic activity, suggesting that JQ1 or a related BET bromodomain inhibitor could greatly improve clinical PDT outcomes for glioblastoma and possibly other malignancies. A few examples of combining JQ1 with conventional radio-or chemotherapeutic approaches have been reported (54,77,78), but the present study represents the first time that JQ1 has been combined with PDT, which is recognized as one of the best treatment options for many solid tumors, including glioblastomas (67)(68)(69). Our findings from this in vitro study provide a strong incentive for more advanced work involving JQ1 in a mouse tumor PDT model, which will soon be underway.…”

Section: Discussionmentioning

confidence: 70%

“…Numerous other examples of combining BET bromodomain inhibitors with conventional chemotherapeutic agents have been described recently, e.g. JQ1 with paclitaxel for triple negative breast cancer (77), and OTX015 with temozolomide for glioblastoma (78). A potential clinical advantage of such combined treatments is that lower than normal individual drug dosages can be used, thus causing less off-target toxicity.…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1

Fahey

Stancill

Smith

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

Endogenous nitric oxide (NO) generated by inducible NO synthase (iNOS) promotes glioblastoma cell proliferation and invasion, and also plays a key role in glioblastoma resistance to chemotherapy and radiotherapy. Non-ionizing photodynamic therapy (PDT) has anti-tumor advantages over conventional glioblastoma therapies. Our previous studies revealed that glioblastoma U87 cells upregulate iNOS after a photodynamic challenge and that resulting NO not only increased resistance to apoptosis, but rendered surviving cells more proliferative and invasive. These findings were largely based on the effects of inhibiting iNOS activity and scavenging NO. Demonstrating now that iNOS expression in photostressed U87 cells is mediated by NF-κB, we hypothesized that (i) recognition of acetylated lysine (acK) on NF-κB p65/Rel A by bromodomain and extra-terminal (BET) protein Brd4 is crucial, and (ii) by suppressing iNOS expression, a BET inhibitor (JQ1) would attenuate the negative effects of photostress. The following evidence was obtained: (i) Like iNOS, Brd4 protein and p65-acK levels increased several fold in photostressed cells; (ii) JQ1 at minimally toxic concentrations had no effect on Brd4 or p65-acK upregulation after PDT, but strongly suppressed iNOS, survivin, and Bcl-xL upregulation, along with the growth and invasion spurt of PDTsurviving cells; (iii) JQ1 inhibition of NO production in photostressed cells closely paralleled that of growth/invasion inhibition; (iv) At 1% the concentration of iNOS inhibitor 1400W, JQ1 reduced post-PDT cell aggressiveness to a far greater extent. This is the first evidence for BET inhibitor targeting of iNOS expression in cancer cells and how such targeting can markedly improve therapeutic efficacy.

show abstract

“…Most cancers rely on multiple drivers for full proliferation, and require drug combinations for effective targeted therapy. Currently, most drug combinations are discovered by empirical testing [18,19], a rational and a mechanism-based platform would greatly aid in the formulation of effective drug combinations. In the current study, we investigated how multi-driver cancer cells respond to targeted therapy, and developed a mathematical model that quantitatively describes the response of multi-driver cancer cells to targeted therapy.…”

Section: Discussionmentioning

confidence: 99%

Biphasic Mathematical Model of Cell–Drug Interaction That Separates Target-Specific and Off-Target Inhibition and Suggests Potent Targeted Drug Combinations for Multi-Driver Colorectal Cancer Cells

Shen

Yang

et al. 2020

Cancers

View full text Add to dashboard Cite

Quantifying the response of cancer cells to a drug, and understanding the mechanistic basis of the response, are the cornerstones for anti-cancer drug discovery. Classical single target-based IC50 measurements are inadequate at describing cancer cell responses to targeted drugs. In this study, based on an analysis of targeted inhibition of colorectal cancer cell lines, we develop a new biphasic mathematical model that accurately describes the cell–drug response. The model describes the drug response using three kinetic parameters: ratio of target-specific inhibition, F1, potency of target-specific inhibition, Kd1, and potency of off-target toxicity, Kd2. Determination of these kinetic parameters also provides a mechanistic basis for predicting effective combination targeted therapy for multi-driver cancer cells. The experiments confirmed that a combination of inhibitors, each blocking a driver pathway and having a distinct target-specific effect, resulted in a potent and synergistic blockade of cell viability, improving potency over mono-agent treatment by one to two orders of magnitude. We further demonstrate that mono-driver cancer cells represent a special scenario in which F1 becomes nearly 100%, and the drug response becomes monophasic. Application of this model to the responses of >400 cell lines to kinase inhibitor dasatinib revealed that the ratio of biphasic versus monophasic responses is about 4:1. This study develops a new mathematical model of quantifying cancer cell response to targeted therapy, and suggests a new framework for developing rational combination targeted therapy for colorectal and other multi-driver cancers.

show abstract

Systematic Drug Screening Identifies Tractable Targeted Combination Therapies in Triple-Negative Breast Cancer

Cited by 42 publications

References 48 publications

MYC-Induced miR-203b-3p and miR-203a-3p Control Bcl-xL Expression and Paclitaxel Sensitivity in Tumor Cells

MYC-Induced miR-203b-3p and miR-203a-3p Control Bcl-xL Expression and Paclitaxel Sensitivity in Tumor Cells

Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1

Biphasic Mathematical Model of Cell–Drug Interaction That Separates Target-Specific and Off-Target Inhibition and Suggests Potent Targeted Drug Combinations for Multi-Driver Colorectal Cancer Cells

Contact Info

Product

Resources

About