Metastasis and Drug Resistance

Fan, Dominic; Langley, Robert L.; Fidler, Isaiah J.

doi:10.1007/978-0-387-89445-4_2

Cited by 6 publications

(4 citation statements)

References 176 publications

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“…Since some studies reported that HER2 mediates tumor growth and metastasis [ 33 , 34 ], and several molecular changes (that could alter tumor aggressiveness) occurred on HER2 and its downstream pathways, we conducted experiments to evaluate such hallmark by measuring cell invasion and adhesion to extracellular matrix (opening metastatic event) capacities of our developed resistant cells ( Fig 1E ). Moreover, several types of resistance such as some chemotherapeutic drugs and multidrug resistance (combining several natural chemotherapeutic drugs) have been associated with cancer invasion and metastasis [ 35 , 36 ]. Hence, we wanted to know if mechanisms of resistance in our anti-HER2 resistant models also turned to a more aggressive phenotype of tumor cells.…”

Section: Resultsmentioning

confidence: 99%

Dual Fatty Acid Synthase and HER2 Signaling Blockade Shows Marked Antitumor Activity against Breast Cancer Models Resistant to Anti-HER2 Drugs

et al. 2015

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Blocking the enzyme Fatty Acid Synthase (FASN) leads to apoptosis of HER2-positive breast carcinoma cells. The hypothesis is that blocking FASN, in combination with anti-HER2 signaling agents, would be an effective antitumor strategy in preclinical HER2+ breast cancer models of trastuzumab and lapatinib resistance. We developed and molecularly characterized in vitro HER2+ models of resistance to trastuzumab (SKTR), lapatinib (SKLR) and both (SKLTR). The cellular interactions of combining anti-FASN polyphenolic compounds (EGCG and the synthetic G28UCM) with anti-HER2 signaling drugs (trastuzumab plus pertuzumab and temsirolimus) were analyzed. Tumor growth inhibition after treatment with EGCG, pertuzumab, temsirolimus or the combination was evaluated in two in vivo orthoxenopatients: one derived from a HER2+ patient and another from a patient who relapsed on trastuzumab and lapatinib-based therapy. SKTR, SKLR and SKLTR showed hyperactivation of EGFR and p-ERK1/2 and PI3KCA mutations. Dual-resistant cells (SKLTR) also showed hyperactivation of HER4 and recovered levels of p-AKT compared with mono-resistant cells. mTOR, p-mTOR and FASN expression remained stable in SKTR, SKLR and SKLTR. In vitro, anti-FASN compounds plus pertuzumab showed synergistic interactions in lapatinib- and dual- resistant cells and improved the results of pertuzumab plus trastuzumab co-treatment. FASN inhibitors combined with temsirolimus displayed the strongest synergistic interactions in resistant cells. In vivo, both orthoxenopatients showed strong response to the antitumor activity of the combination of EGCG with pertuzumab or temsirolimus, without signs of toxicity. We showed that the simultaneous blockade of FASN and HER2 pathways is effective in cells and in breast cancer models refractory to anti-HER2 therapies.

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Section: Resultsmentioning

confidence: 99%

Dual Fatty Acid Synthase and HER2 Signaling Blockade Shows Marked Antitumor Activity against Breast Cancer Models Resistant to Anti-HER2 Drugs

et al. 2015

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“…The goal of this study was to further understand pathways/molecules involved in the response of TNBCs to PTX. Although TNBCs as a group are especially sensitive to taxanes, some taxane‐treated TNBC patients relapse and develop lethal metastatic disease . It is therefore important to understand the mechanisms of taxane resistance in TNBC cells that give rise to metastatic disease; this may lead to the development of biomarkers that can predict how TNBC patients will respond to PTX therapy.…”

Section: Discussionmentioning

confidence: 99%

A novel EGR‐1 dependent mechanism for YB‐1 modulation of paclitaxel response in a triple negative breast cancer cell line

Lasham

Mehta

Fitzgerald

et al. 2016

Intl Journal of Cancer

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Chemotherapy with taxanes such as paclitaxel (PTX) is a key component of triple negative breast cancer (TNBC) treatment. PTX is used in combination with other drugs in both the adjuvant setting and in advanced breast cancer. Because a proportion of patients respond poorly to PTX or relapse after its use, a greater understanding of the mechanisms conferring resistance to PTX is required. One protein shown to be involved in drug resistance is Y-box binding protein 1 (YB-1). High levels of YB-1 have previously been associated with resistance to PTX in TNBCs. In this study, we aimed to determine mechanisms by which YB-1 confers PTX resistance. We generated isogenic TNBC cell lines that differed by YB-1 levels and treated these with PTX. Using microarray analysis, we identified EGR1 as a potential target of YB-1. We found that low EGR1 mRNA levels are associated with poor breast cancer patient prognosis, and that EGR1 and YBX1 mRNA expression was inversely correlated in a TNBC line and in a proportion of TNBC tumours. Reducing the levels of EGR1 caused TNBC cells to become more resistant to PTX. Given that PTX targets cycling cells, we propose a model whereby high YB-1 levels in some TNBC cells can lead to reduced levels of EGR1, which in turn promotes slow cell cycling and resistance to PTX. Therefore YB-1 and EGR1 levels are biologically linked and may provide a biomarker for TNBC response to PTX.

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“…In comparison, acquired resistance develops after an initial exposure to chemotherapeutics. Multidrug resistance (MDR) can emerge as a cellular response to chemotherapeutic agents . The family of proteins known as MDR-associated proteins (MRPs) are often organic anion transporters, although MRP1, MRP2, and MRP3 can also transport neutral molecules, which function as efflux pumps in order to reduce intracellular drug concentrations.…”

Section: Cancer and Redox Chemistrymentioning

confidence: 99%

Next-Generation Metal Anticancer Complexes: Multitargeting via Redox Modulation

2013

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Platinum complexes are widely used anticancer drugs. New generations of metal chemotherapeutics offer the prospect of combating platinum resistance and expanding the range of treatable cancers. Such new complexes might be effective if they form distinctly different lesions on DNA. In this Forum Article, we discuss the possibility that targeting the redox balance in cancer cells may also be a highly effective strategy, especially because it is a multiple-site approach and offers selectivity over normal cells. Metal complexes can interfere in cellular redox chemistry in several ways: directly through metal or ligand redox centers or indirectly by binding to biomolecules involved in cellular redox pathways. We illustrate that a surprisingly large number of active metal anticancer agents have a potential redox arm to their mechanism of action. For such complexes, the possibility arises of using combination therapy together with redox modulators to increase the anticancer potency: attractive for lowering the doses of metal complexes that need to be administered. We illustrate that organometallic ruthenium(II) and osmium(II) arene complexes and iridium(III) cyclopentadienyl complexes of the type [(arene/Cp(xPh))M(N,N)Cl/I](n+) can achieve nanomolar potency toward cancer cells in combination with the redox modulator l-buthionine sulfoximine. Our discussion highlights the importance of determining not only the distribution of metal anticancer complexes in cells but also their speciation, the chemical form of the metal complex, including the oxidation state of the metal, the fate of the ligands, and dynamic processes such as efflux. This will be aided in the future by proteomic and genomic analyses but needs to be supplemented by new analytical methods that have the sensitivity and spatial and temporal resolution to reveal such information. To achieve this, major new funding programs are needed that support global research on the design of novel metal-based drugs with new mechanisms of action, tailored to patient needs.

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Metastasis and Drug Resistance

Cited by 6 publications

References 176 publications

Dual Fatty Acid Synthase and HER2 Signaling Blockade Shows Marked Antitumor Activity against Breast Cancer Models Resistant to Anti-HER2 Drugs

Dual Fatty Acid Synthase and HER2 Signaling Blockade Shows Marked Antitumor Activity against Breast Cancer Models Resistant to Anti-HER2 Drugs

A novel EGR‐1 dependent mechanism for YB‐1 modulation of paclitaxel response in a triple negative breast cancer cell line

Next-Generation Metal Anticancer Complexes: Multitargeting via Redox Modulation

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