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MiR-205 as predictive biomarker and adjuvant therapeutic tool in combination with trastuzumab.
Authors: Cataldo A, Piovan C, Plantamura I, D'Ippolito E, Camelliti S, Casalini P, Giussani M, Déas O, Cairo S, Judde JG, Tagliabue E, Iorio MV Abstract Trastuzumab is the standard treatment for HER2+ breast cancer (BC) patients, and even though it significantly improved their clinical outcome, 50% of them do not benefit from this drug and disease recurs, underlining the need of reliable predictive biomarkers and new therapeutic strategies. Strikingly, despite all the molecular analyses performed to identify the escape mechanisms behind this resistance, it still represents a question point. MiRNAs have been correl...
Source: Oncotarget - July 4, 2018 Category: Cancer & Oncology Tags: Oncotarget Source Type: research

Oncodriver inhibition and CD4+ Th1 cytokines cooperate through Stat1 activation to induce tumor senescence and apoptosis in HER2+ and triple negative breast cancer: implications for combining immune and targeted therapies.
Authors: Rosemblit C, Datta J, Lowenfeld L, Xu S, Basu A, Kodumudi K, Wiener D, Czerniecki BJ Abstract In patients with HER2-expressing breast cancer many develop resistance to HER2 targeted therapies. We show that high and intermediate HER2-expressing cancer cell lines are driven toward apoptosis and tumor senescence when treated with either CD4+ Th1 cells, or Th1 cytokines TNF-α and IFN-γ, in a dose dependent manner. Depletion of HER2 activity by either siRNA or trastuzumab and pertuzumab, and subsequent treatment with either anti-HER2 Th1 cells or TNF-α and IFN-γ resulted in synergistic increased tumor senes...
Source: Oncotarget - May 31, 2018 Category: Cancer & Oncology Tags: Oncotarget Source Type: research

t-Darpp activates IGF-1R signaling to regulate glucose metabolism in trastuzumab-resistant breast cancer cells.
CONCLUSIONS: t-Darpp activates IGF-1R signaling through heterodimerization with EGFR and HER2 to stimulate glycolysis and confer trastuzumab resistance. PMID: 29180608 [PubMed - as supplied by publisher]
Source: Clinical Cancer Research - November 27, 2017 Category: Cancer & Oncology Authors: Lenz G, Hamilton A, Geng S, Hong T, Kalkum M, Momand J, Kane SE, Huss J Tags: Clin Cancer Res Source Type: research

FEN1 knockdown improves trastuzumab sensitivity in human epidermal growth factor 2-positive breast cancer cells.
Authors: Zeng X, Che X, Liu YP, Qu XJ, Xu L, Zhao CY, Zheng CL, Hou KZ, Teng Y Abstract Trastuzumab has been widely applied as a treatment for human epidermal growth factor 2 (HER2)-overexpressing breast cancer. However, the therapeutic efficacy of trastuzumab is limited. Flap endonuclease 1 (FEN1) is a multifunctional endonuclease that has a crucial role in DNA recombination and repair. Inhibition of FEN1 is associated with the reversal of anticancer drug resistance. However, it is unclear whether FEN1 is involved in trastuzumab resistance. In the present study, it was demonstrated that trastuzumab increases the e...
Source: Experimental and Therapeutic Medicine - September 17, 2017 Category: General Medicine Tags: Exp Ther Med Source Type: research

Defective cyclin B1 induction in trastuzumab-emtansine (T-DM1) acquired resistance in HER2-positive breast cancer.
Conclusion: Defective cyclin B1 induction by T-DM1 mediates acquired resistance in HER2 positive breast cancer cells. These results support the testing of cyclin B1 induction upon         T-DM1 treatment as a pharmacodynamic predictor in HER2 positive breast cancer. PMID: 28821558 [PubMed - as supplied by publisher]
Source: Clinical Cancer Research - August 18, 2017 Category: Cancer & Oncology Authors: Sabbaghi M, Gil-Gómez G, Guardia C, Servitja S, Arpi O, García-Alonso S, Menéndez S, Arumi-Uria M, Serrano L, Salido M, Muntasell A, Martinez-Garcia M, Zazo S, Chamizo C, González-Alonso P, Madoz-Gúrpide J, Eroles P, Arribas J, Tusquets I, Lluch A, P Tags: Clin Cancer Res Source Type: research

Activation of STAT3/HIF-1 α/Hes-1 axis promotes trastuzumab resistance in HER2-overexpressing breast cancer cells via down-regulation of PTEN
Conclusion The impairment of STAT3-HIF-1α-HES-1 pathway restored trastuzumab sensitivity through up-regulation of PTEN protein. General significance These findings highlighted the signal integrator role of HIF-1α in STAT3-mediated trastuzumab resistance induction which would be valuable in designing more efficient chemosensitization strategies. Graphical abstract
Source: Biochimica et Biophysica Acta (BBA) General Subjects - May 28, 2017 Category: Biochemistry Source Type: research

HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2+ Breast Cancer.
Conclusion: HER2 reactivation through acquisition of the HER2L755S mutation was identified as a mechanism of acquired resistance to L-containing HER2-targeted therapy in preclinical HER2-amplified breast cancer models, which can be overcome by irreversible HER1/2 inhibitors. PMID: 28487443 [PubMed - as supplied by publisher]
Source: Clinical Cancer Research - May 9, 2017 Category: Cancer & Oncology Authors: Xu X, De Angelis C, Burke KA, Nardone A, Hu H, Qin L, Veeraraghavan J, Sethunath V, Heiser LM, Wang NJ, Ng CKY, Chen E, Renwick A, Wang T, Nanda S, Shea M, Mitchell T, Rajendran M, Waters I, Zabransky DJ, Scott KL, Gutierrez C, Nagi C, Geyer FC, Chamness Tags: Clin Cancer Res Source Type: research

Activation of STAT3/HIF-1 α/Hes-1 axis promotes Trastuzumab resistance in HER2- overexpressing Breast cancer cells via down-regulation of PTEN.
CONCLUSION: The impairment of STAT3-HIF-1α-HES-1 pathway restored trastuzumab sensitivity through up-regulation of PTEN protein. GENERAL SIGNIFICANCE: These findings highlighted the signal integrator role of HIF-1α in STAT3-mediated trastuzumab resistance induction which would be valuable in designing more efficient chemosensitization strategies. PMID: 28499822 [PubMed - as supplied by publisher]
Source: Biochimica et Biophysica Acta - May 9, 2017 Category: Biochemistry Authors: Aghazadeh S, Yazdanparast R Tags: Biochim Biophys Acta Source Type: research

Activation of STAT3/HIF-1 α/Hes-1 axis promotes Trastuzumab resistance in HER2- overexpressing Breast cancer cells via down-regulation of PTEN
Conclusion The impairment of STAT3-HIF-1α-HES-1 pathway restored trastuzumab sensitivity through up-regulation of PTEN protein. General significance These findings highlighted the signal integrator role of HIF-1α in STAT3-mediated trastuzumab resistance induction which would be valuable in designing more efficient chemosensitization strategies. Graphical abstract
Source: Biochimica et Biophysica Acta (BBA) General Subjects - May 9, 2017 Category: Biochemistry Source Type: research

Activating ERBB2/HER2 mutations indicate susceptibility to pan-HER inhibitors in Lynch and Lynch-like colorectal cancer
Conclusions We developed a high-throughput deep sequencing approach for concomitant MSI and mutational analyses in FFPE specimens. We provided novel insights into clinically relevant alterations in MSI CRC and a rationale for targeting ERBB2/HER2 mutations in Lynch and Lynch-like CRC.
Source: Gut - July 7, 2016 Category: Gastroenterology Authors: Kloth, M., Ruesseler, V., Engel, C., Koenig, K., Peifer, M., Mariotti, E., Kuenstlinger, H., Florin, A., Rommerscheidt-Fuss, U., Koitzsch, U., Wodtke, C., Ueckeroth, F., Holzapfel, S., Aretz, S., Propping, P., Loeffler, M., Merkelbach-Bruse, S., Odenthal, Tags: Colon cancer Source Type: research

Novel cancer stem cell targets during epithelial to mesenchymal transition in PTEN-deficient trastuzumab-resistant breast cancer.
Authors: Sun L, Burnett J, Gasparyan M, Xu F, Jiang H, Lin CC, Myers I, Korkaya H, Liu Y, Connarn J, He H, Zhang N, Wicha MS, Sun D Abstract Continued use of trastuzumab in PTEN-deficient HER2+ breast cancer induces the epithelial-to-mesenchymal transition (EMT), transforms HER2+ to triple negative breast cancer, and expands breast cancer stem cells (BCSCs). Using cancer cell lines with two distinct states, epithelial and mesenchymal, we identified novel targets during EMT in PTEN-deficient trastuzumab-resistant breast cancer. Differential gene expression and distinct responses to a small molecule in BT474 (HER2+ t...
Source: Oncotarget - June 11, 2016 Category: Cancer & Oncology Tags: Oncotarget Source Type: research

A combination of trastuzumab and BAG-1 inhibition synergistically targets HER2 positive breast cancer cells.
This study investigated the therapeutic potential of targeting the BAG-1 protein co-chaperone in trastuzumab-responsive or -resistant cells. In the METABRIC dataset, BAG-1 mRNA was significantly elevated in HER2+ breast tumors and predicted overall survival in a multivariate analysis (HR = 0.81; p = 0.022). In a breast cell line panel, BAG-1 protein was increased in HER2+ cells and was required for optimal growth as shown by siRNA knockdown. Overexpression of BAG-1S in HER2+ SKBR3 cells blocked growth inhibition by trastuzumab, whereas overexpression of a mutant BAG-1S protein (BAG-1S H3AB), defective in binding HSC70, pot...
Source: Oncotarget - March 10, 2016 Category: Cancer & Oncology Tags: Oncotarget Source Type: research

Therapeutic siRNA for drug-resistant HER2-positive breast cancer.
Authors: Gu S, Hu Z, Ngamcherdtrakul W, Castro DJ, Morry J, Reda MM, Gray JW, Yantasee W Abstract HER2 is overexpressed in about 20% of breast cancers and contributes to poor prognosis. Unfortunately, a large fraction of patients have primary or acquired resistance to the HER2-targeted therapy trastuzumab, thus a multi-drug combination is utilized in the clinic, putting significant burden on patients. We systematically identified an optimal HER2 siRNA from 76 potential sequences and demonstrated its utility in overcoming intrinsic and acquired resistance to trastuzumab and lapatinib in 18 HER2-positive cancer cell ...
Source: Oncotarget - February 21, 2016 Category: Cancer & Oncology Tags: Oncotarget Source Type: research

Abstract P5-04-17: From transcriptome meta-analysis to targeted therapies in triple negative breast cancer
Triple-Negative Breast Cancer (TNBC) is a subtype of breast cancer that urgently requires the identification and approval of novel targeted therapies. Even for breast cancer subtypes that have approved targeted therapies such as tamoxifen in ER+ and herceptin in HER2+ patients, there are a proportion of patients that do not respond to these therapies or develop resistance and succumb to metastatic recurrence. Thus, there is a clinical need to identify patients who do not benefit from current standard therapies and developing new strategies for therapy for non-responsive patients across all breast cancer subtypes.We hypothe...
Source: Cancer Research - February 18, 2016 Category: Cancer & Oncology Authors: Rozali, E., Al-Ejeh, F. Tags: Poster Session Abstracts Source Type: research

Abstract P5-08-22: DUSP4 is associated with increased resistance against anti-HER2 therapy in breast cancer
Conclusions. Our findings suggest that DUSP4 is involved in the development of trastuzumab resistance in HER2 positive BC.Citation Format: Györffy B, Munkacsy G, Esteva FJ, Miquel TP, Menyhart O. DUSP4 is associated with increased resistance against anti-HER2 therapy in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-22.
Source: Cancer Research - February 18, 2016 Category: Cancer & Oncology Authors: Gyorffy, B., Munkacsy, G., Esteva, F., Miquel, T., Menyhart, O. Tags: Poster Session Abstracts Source Type: research

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