<b>Intratumor lactate levels reflect HER2 addiction status in HER2‐positive breast cancer</b>

Castagnoli, Lorenzo; Iorio, Egidio; Dugo, Matteo; Koschorke, Ada; Faraci, Simona; Canese, Rossella; Casalini, Patrizia; Nanni, Patrizia; Vernieri, Claudio; Nicola, Massimo Di; Morelli, Daniele; Tagliabue, Elda; Pupa, Serenella M.

doi:10.1002/jcp.27049

Cited by 35 publications

(33 citation statements)

References 47 publications

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“…Together these data highlight the existence of a metabolic reprogramming that is dependent on the HER2 status of the ER + cell lines analyzed, suggesting potential therapeutic scenarios that may differ based on the expression of HER2 on the subset of the cells analyzed. These data are in line with previous studies showing that targeting glycolysis may have a synergistic effect in HER2 + breast cancer in combination with anti-HER2 therapy [23][24][25]. (A, C, E, G) PDS (either in presence or absence of 1 µM palbociclib, PD) and PDR cells were subjected to seahorse XFe96 glycolytic rate analysis and glycolytic proton efflux rate (glycoPER)) was measured in real time and normalized on protein levels.…”

Section: Human Epidermal Growth Factor Receptor 2 (Her2) Status Impacsupporting

confidence: 88%

Glucose Metabolic Reprogramming of ER Breast Cancer in Acquired Resistance to the CDK4/6 Inhibitor Palbociclib+

Lorito

Bacci

Smiriglia

et al. 2020

Cells

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The majority of breast cancers express the estrogen receptor (ER) and are dependent on estrogen for their growth and survival. Endocrine therapy (ET) is the standard of care for these tumors. However, a superior outcome is achieved in a subset of ER positive (ER+)/human epidermal growth factor receptor 2 negative (HER2−) metastatic breast cancer patients when ET is administrated in combination with a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor, such as palbociclib. Moreover, CDK4/6 inhibitors are currently being tested in ER+/HER2+ breast cancer and reported encouraging results. Despite the clinical advances of a combinatorial therapy using ET plus CDK4/6 inhibitors, potential limitations (i.e., resistance) could emerge and the metabolic adaptations underlying such resistance warrant further elucidation. Here we investigate the glucose-dependent catabolism in a series of isogenic ER+ breast cancer cell lines sensitive to palbociclib and in their derivatives with acquired resistance to the drug. Importantly, ER+/HER2− and ER+/HER2+ cell lines show a different degree of glucose dependency. While ER+/HER2− breast cancer cells are characterized by enhanced aerobic glycolysis at the time of palbociclib sensitivity, ER+/HER2+ cells enhance their glycolytic catabolism at resistance. This metabolic phenotype was shown to have prognostic value and was targeted with multiple approaches offering a series of potential scenarios that could be of clinical relevance.

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Section: Human Epidermal Growth Factor Receptor 2 (Her2) Status Impacsupporting

confidence: 88%

Glucose Metabolic Reprogramming of ER Breast Cancer in Acquired Resistance to the CDK4/6 Inhibitor Palbociclib+

Lorito

Bacci

Smiriglia

et al. 2020

Cells

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“…In BC, the association of PKM2 with VEGF-C was investigated in 218 BC patients in whom the mRNA levels of both were upregulated in tumor tissue compared to regular counterparts [ 123 ]. Moreover, the knockdown of PKM2 inhibited glycolysis and protein levels of VEGF-C, which subsequently reduced cancer cell proliferation in BC MCF-7 and MDA-MB-231 cells [ 124 ]. Combined expression of the above proteins in the clinical samples was associated with worse histological grade, lymph node metastasis, lymphovascular invasion, and poor patient survival [ 123 , 125 ].…”

Section: Altered Glucose Metabolism and Anticancer Drug Resistancementioning

confidence: 99%

“…Combined expression of the above proteins in the clinical samples was associated with worse histological grade, lymph node metastasis, lymphovascular invasion, and poor patient survival [ 123 , 125 ]. Besides, the analysis of PKM1 and PKM2 expression in TNBC showed high expression of both proteins and targeting PK inhibited the proliferation of TNBC MDA-MB-231 and MDA-MB-436 cells via inhibiting NFκB signaling pathway [ 124 ]. Clinical studies reported a correlation between PKM2 expression and the prediction of chemosensitivity to epirubicin and 5-flurouracil (5-FU) based on the immunohistochemical analysis done in 296 patients diagnosed with invasive BC [ 126 ].…”

Section: Altered Glucose Metabolism and Anticancer Drug Resistancementioning

confidence: 99%

“…Thus, trastuzumab, along with PI3K/AKT inhibitors, potentially increases the efficacy of cancer treatment [ 205 ]. A study of the molecular mechanism of trastuzumab action demonstrated inhibition of aerobic glycolysis via ErbB2-heat shock factor 1 (HSF1)-LDHA pathway ( Figure 2 E) while the sensitivity to trastuzumab was associated with LDHA activity [ 124 ]. HSF1 transcriptionally regulates LDHA, and a knockdown of HSF1 was associated with repressed LDHA expression in BC BT474 and SKBR3 cells ( Figure 2 E).…”

Section: Modulating Glucose Metabolism To Increase the Anticancer mentioning

confidence: 99%

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Targeting Glucose Metabolism to Overcome Resistance to Anticancer Chemotherapy in Breast Cancer

Varghese

Samuel

Líšková

et al. 2020

Cancers

126

101

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Breast cancer (BC) is the most prevalent cancer in women. BC is heterogeneous, with distinct phenotypical and morphological characteristics. These are based on their gene expression profiles, which divide BC into different subtypes, among which the triple-negative breast cancer (TNBC) subtype is the most aggressive one. The growing interest in tumor metabolism emphasizes the role of altered glucose metabolism in driving cancer progression, response to cancer treatment, and its distinct role in therapy resistance. Alterations in glucose metabolism are characterized by increased uptake of glucose, hyperactivated glycolysis, decreased oxidative phosphorylation (OXPHOS) component, and the accumulation of lactate. These deviations are attributed to the upregulation of key glycolytic enzymes and transporters of the glucose metabolic pathway. Key glycolytic enzymes such as hexokinase, lactate dehydrogenase, and enolase are upregulated, thereby conferring resistance towards drugs such as cisplatin, paclitaxel, tamoxifen, and doxorubicin. Besides, drug efflux and detoxification are two energy-dependent mechanisms contributing to resistance. The emergence of resistance to chemotherapy can occur at an early or later stage of the treatment, thus limiting the success and outcome of the therapy. Therefore, understanding the aberrant glucose metabolism in tumors and its link in conferring therapy resistance is essential. Using combinatory treatment with metabolic inhibitors, for example, 2-deoxy-D-glucose (2-DG) and metformin, showed promising results in countering therapy resistance. Newer drug designs such as drugs conjugated to sugars or peptides that utilize the enhanced expression of tumor cell glucose transporters offer selective and efficient drug delivery to cancer cells with less toxicity to healthy cells. Last but not least, naturally occurring compounds of plants defined as phytochemicals manifest a promising approach for the eradication of cancer cells via suppression of essential enzymes or other compartments associated with glycolysis. Their benefits for human health open new opportunities in therapeutic intervention, either alone or in combination with chemotherapeutic drugs. Importantly, phytochemicals as efficacious instruments of anticancer therapy can suppress events leading to chemoresistance of cancer cells. Here, we review the current knowledge of altered glucose metabolism in contributing to resistance to classical anticancer drugs in BC treatment and various ways to target the aberrant metabolism that will serve as a promising strategy for chemosensitizing tumors and overcoming resistance in BC.

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“…In particular, the d16HER2 splice variant, which is expressed as a proportion (approximately 2–9%) of WTHER2 in human HER2-positive BC 18,19 , may have a crucial pathobiological role given that the post-transcriptional loss of 48 nucleotides in the extracellular domain induces the formation of stable and constitutively active HER2 homodimers on the tumor cell surface 18,20 . d16HER2 influences not only tumor aggressiveness and trastuzumab susceptibility 19,21 but also stem properties 22 and the metabolic profile 23 of HER2-positive BC cells. Indeed, d16HER2 expression/activation strongly reflects a status of HER2 oncogenic signaling dependence (HER2 addiction) 19,23–25 , representing a novel and potentially clinically useful biomarker.…”

Section: Introductionmentioning

confidence: 99%

The landscape of d16HER2 splice variant expression across HER2-positive cancers

Volpi

Pietrantonio

Gloghini

et al. 2019

Sci Rep

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The HER2 splice variant characterized by the deletion of exon 16 and denominated as d16HER2, is associated with HER2-positive breast cancer (BC) aggressiveness, stemness, and trastuzumab susceptibility and is considered to be a “flag” of HER2 dependence. However, with the exception of quantitative real-time PCR analysis, easily reproducible assays are still lacking to clinically detect and quantify the d16HER2 expression. Further, no data on d16HER2 expression and its potential role are available in HER2-positive gastrointestinal malignancies. Here, we used a novel RNA in situ hybridization technique (BaseScope) to discriminate d16HER2 variant expression from the wild type isoform (WTHER2) and to assess their levels across different HER2-positive histological samples. Our results demonstrate the existence of outliers, with d16HER2 mRNA high scores restricted to HER2-positive gastric cancer (GC) and colorectal cancer (CRC) coupled with increased d16HER2 expression compared with BC. Consistent with previously reported data on BC, experiments performed in HER2-positive GC patient-derived xenografts suggest that increased d16HER2 expression is associated with a clinical benefit/response to single-agent trastuzumab. Therefore, d16HER2 may be considered as a “flag” of HER2 dependence in GC and can be clinically investigated as a marker of trastuzumab susceptibility in several other HER2-driven cancers, including CRC. As a clinical proof-of-concept, we indicate that high d16HER2 mRNA scores are exclusively found in patients with a long-term benefit from trastuzumab exceeding 12 months (clinical “outliers”), and that d16HER2 expression is also increased in circulating tumor-released exosomes obtained from baseline plasma samples of long-term responders.

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Intratumor lactate levels reflect HER2 addiction status in HER2‐positive breast cancer

Cited by 35 publications

References 47 publications

Glucose Metabolic Reprogramming of ER Breast Cancer in Acquired Resistance to the CDK4/6 Inhibitor Palbociclib+

Glucose Metabolic Reprogramming of ER Breast Cancer in Acquired Resistance to the CDK4/6 Inhibitor Palbociclib+

Targeting Glucose Metabolism to Overcome Resistance to Anticancer Chemotherapy in Breast Cancer

The landscape of d16HER2 splice variant expression across HER2-positive cancers

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