Dual PI3K and Wnt pathway inhibition is a synergistic combination against triple negative breast cancer

Solzak, Jeffrey P.; Atale, Rutuja; Hancock, Bradley A.; Sinn, Anthony L.; Pollok, Karen E.; Jones, David R.; Radovich, Milan

doi:10.1038/s41523-017-0016-8

Cited by 44 publications

(31 citation statements)

References 40 publications

(38 reference statements)

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“…PI3K inhibition promotes the expression of Wnt ligands in breast cancers, whereas BRAF inhibition upregulates b-catenin signaling through activating the focal adhesion kinase in colorectal cancer. Blocking Wnt/b-catenin signaling by tankyrase inhibitor or PORCN inhibitor can significantly enhance the tumor suppression effect of these small molecular inhibitors targeting the growth factor signaling pathways (Tzeng et al, 2015;Solzak et al, 2017;Chen et al, 2018;Solberg et al, 2018). In EGFRmutated lung cancer, even though EGFR inhibitors are not observed to significantly upregulate Wnt signaling in preclinical studies, Wnt/b-catenin signaling has been shown to drive resistance to EGFR inhibitors in lung cancer cells because tankyrase inhibitor and EGFR inhibitor in combination can synergistically suppress lung cancer cell growth in vitro and in vivo (Casás-Selves et al, 2012;Scarborough et al, 2017).…”

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confidence: 99%

Wnt Signaling and Drug Resistance in Cancer

2019

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Wnts are secreted proteins that bind to cell surface receptors to activate downstream signaling cascades. Normal Wnt signaling plays key roles in embryonic development and adult tissue homeostasis. The secretion of Wnt ligands, the turnover of Wnt receptors, and the signaling transduction are tightly regulated and fine-tuned to keep the signaling output "just right." Hyperactivated Wnt signaling due to recurrent genetic alterations drives several human cancers. Elevated Wnt signaling also confers resistance to multiple conventional and targeted cancer therapies through diverse mechanisms including maintaining the cancer stem cell population, enhancing DNA damage repair, facilitating transcriptional plasticity, and promoting immune evasion. Different classes of Wnt signaling inhibitors targeting key nodes of the pathway have been developed and show efficacy in treating Wnt-driven cancers and subverting Wnt-mediated therapy resistance in preclinical studies. Several of these inhibitors have advanced to clinical trials, both singly and in combination with other existing US Food and Drug Administration-approved anti-cancer modalities. In the near future, pharmacological inhibition of Wnt signaling may be a real choice for patients with cancer. SIGNIFICANCE STATEMENTThe latest insights in Wnt signaling, ranging from basic biology to therapeutic implications in cancer, are reviewed. Recent studies extend understanding of this ancient signaling pathway and describe the development and improvement of anti-Wnt therapeutic modalities for cancer.

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confidence: 99%

Wnt Signaling and Drug Resistance in Cancer

2019

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“…We next used publicly available cancer transcriptome data set (as described by Solzak et al 44 ) to determine whether the genes targeted by the combination treatments (DEGs) are known to be differentially expressed in triple‐negative breast cancer patients and therefore potentially important for the cancer state. Although the overlap between the genes which were up‐regulated by SAM + 5AzadC but down‐regulated in patients was not significant as determined by a hypergeometric test (Figure 4C), there was a significant overlap of 71 genes which were down‐regulated by SAM + 5AzadC treatment with the set of genes which were up‐regulated in breast cancer patients (hypergeometric test, P < 0.05) (Figure 4D).…”

Section: Resultsmentioning

confidence: 99%

S‐adenosylmethionine in combination with decitabine shows enhanced anti‐cancer effects in repressing breast cancer growth and metastasis

Mahmood

Arakelian

Cheishvili

et al. 2020

J Cellular Molecular Medi

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Abnormal DNA methylation orchestrates many of the cancer‐related gene expression irregularities such as the inactivation of tumour suppressor genes through hypermethylation as well as activation of prometastatic genes through hypomethylation. The fact that DNA methylation abnormalities can be chemically reversed positions the DNA methylation machinery as an attractive target for anti‐cancer drug development. However, although in vitro studies suggested that targeting concordantly hypo‐ and hypermethylation is of benefit in suppressing both oncogenic and prometastatic functions of breast cancer cells, this has never been tested in a therapeutic setting in vivo. In this context, we investigated the combined therapeutic effects of an approved nutraceutical agent S‐adenosylmethionine (SAM) and FDA‐approved hypomethylating agent decitabine using the MDA‐MB‐231 xenograft model of breast cancer and found a pronounced reduction in mammary tumour volume and lung metastasis compared to the animals in the control and monotherapy treatment arms. Immunohistochemical assessment of the primary breast tumours showed a significantly reduced expression of proliferation (Ki‐67) and angiogenesis (CD31) markers following combination therapy as compared to the control group. Global transcriptome and methylome analyses have revealed that the combination therapy regulates genes from several key cancer‐related pathways that are abnormally expressed in breast tumours. To our knowledge, this is the first preclinical study demonstrating the anti‐cancer therapeutic potential of using a combination of methylating (SAM) and demethylating agent (decitabine) in vivo. Results from this study provide a molecularly founded rationale for clinically testing a combination of agents targeting the epigenome to reduce the morbidity and mortality from breast cancer.

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“…SRI35889 and to a lesser extent, SRI33576, were found to inhibit mTOR signaling in addition to Wnt/β-catenin activity, which may confer increased cytotoxic potency in TNBC. Recently, a study supported the use of dual inhibition of both PI3K/AKT/mTOR and Wnt/β-catenin pathways for synergistic effects in TNBC [ 70 ]. Interestingly, treatment of TNBC with the pan-PI3K inhibitor buparlisib increased Wnt/β-catenin activity via increased expression of Wnt/β-catenin pathway mediators such as FZDs, Wnt ligands, LRP4/6 and porcupine.…”

Section: Discussionmentioning

confidence: 99%

Preferential Inhibition of Wnt/β-Catenin Signaling by Novel Benzimidazole Compounds in Triple-Negative Breast Cancer

Gangrade

Pathak

Augelli‐Szafran

et al. 2018

IJMS

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Wnt/β-catenin signaling is upregulated in triple-negative breast cancer (TNBC) compared to other breast cancer subtypes and normal tissues. Current Wnt/β-catenin inhibitors, such as niclosamide, target the pathway nonspecifically and exhibit poor pharmacokinetics/pharmacodynamics in vivo. Niclosamide targets other pathways, including mTOR, STAT3 and Notch. Novel benzimidazoles have been developed to inhibit Wnt/β-catenin signaling with greater specificity. The compounds SRI33576 and SRI35889 were discovered to produce more cytotoxicity in TNBC cell lines than in noncancerous cells. The agents also downregulated Wnt/β-catenin signaling mediators LRP6, cyclin D1, survivin and nuclear active β-catenin. In addition, SRI33576 did not affect mTOR, STAT3 and Notch signaling in TNBC and noncancerous cells. SRI35889 inhibited mTOR signaling less in noncancerous than in cancerous cells, while not affecting STAT3 and Notch pathways. Compounds SRI32529, SRI35357 and SRI35361 were not selectively cytotoxic against TNBC cell lines compared to MCF10A cells. While SRI32529 inhibited Wnt/β-catenin signaling, the compound also mitigated mTOR, STAT3 and Notch signaling. SRI33576 and SRI35889 were identified as cytotoxic and selective inhibitors of Wnt/β-catenin signaling with therapeutic potential to treat TNBC in vivo.

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Dual PI3K and Wnt pathway inhibition is a synergistic combination against triple negative breast cancer

Cited by 44 publications

References 40 publications

Wnt Signaling and Drug Resistance in Cancer

Wnt Signaling and Drug Resistance in Cancer

S‐adenosylmethionine in combination with decitabine shows enhanced anti‐cancer effects in repressing breast cancer growth and metastasis

Preferential Inhibition of Wnt/β-Catenin Signaling by Novel Benzimidazole Compounds in Triple-Negative Breast Cancer

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