TNFα-Induced Mucin 4 Expression Elicits Trastuzumab Resistance in HER2-Positive Breast Cancer

Mercogliano, María F.; Martino, Mara De; Venturutti, Leandro; Rivas, Martín A.; Proietti, Cecilia J.; Inurrigarro, Gloria; Frahm, Isabel; Allemand, Daniel H.; Deza, Ernesto Gil; Ares, Sandra; Gercovich, Felipe G.; Guzmán, Pablo; Roa, Juan Carlos; Elizalde, Patricia V.; Schillaci, Roxana

doi:10.1158/1078-0432.ccr-16-0970

Cited by 92 publications

(101 citation statements)

References 43 publications

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“…13B). Consistent with cell line-based studies reported in the literature [30][31][32][33] trastuzumab induced tumor regression in mucin negative WHIM8 but not in mucin positive WHIM35 (Fig. 5f).…”

Section: Articlesupporting

confidence: 91%

Microscaled proteogenomic methods for precision oncology

et al. 2020

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Cancer proteogenomics promises new insights into cancer biology and treatment efficacy by integrating genomics, transcriptomics and protein profiling including modifications by mass spectrometry (MS). A critical limitation is sample input requirements that exceed many sources of clinically important material. Here we report a proteogenomics approach for core biopsies using tissue-sparing specimen processing and microscaled proteomics. As a demonstration, we analyze core needle biopsies from ERBB2 positive breast cancers before and 48-72 h after initiating neoadjuvant trastuzumab-based chemotherapy. We show greater suppression of ERBB2 protein and both ERBB2 and mTOR target phosphosite levels in cases associated with pathological complete response, and identify potential causes of treatment resistance including the absence of ERBB2 amplification, insufficient ERBB2 activity for therapeutic sensitivity despite ERBB2 amplification, and candidate resistance mechanisms including androgen receptor signaling, mucin overexpression and an inactive immune microenvironment. The clinical utility and discovery potential of proteogenomics at biopsyscale warrants further investigation.

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Section: Articlesupporting

confidence: 91%

Microscaled proteogenomic methods for precision oncology

et al. 2020

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“…Interestingly, WHIM35 has high expression of mucin proteins compared to WHIM8 (Supplementary Figure 13A) indicating this case was a phenocopy of BCN1369 (Supplementary Figure 13B). Consistent with cell line-based studies reported in the literature [30][31][32][33] that proposed that mucin expression might inhibit trastuzumab-mediated response, trastuzumab induced tumor regression in WHIM8 but not in WHIM35 ( Figure 5F). Drawing from the observation that BCN1369 also exhibited elevated PI3K-Akt-mTOR signaling ( Figure 5B), together with a recent report that showed mTOR mediated MUC1 induction in multiple breast cancer cell lines 30 , these PDX models were additionally treated with the small molecule mTOR inhibitor everolimus.…”

Section: Proteomics and Phosphoproteomic Analyses Of Acute On-treatmesupporting

confidence: 90%

Microscaled Proteogenomic Methods for Precision Oncology

Satpathy

Jaehnig

Krug

et al. 2019

Preprint

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and MJE: Matthew.Ellis@bcm.edu Running title: Microscaled Proteogenomic Methods for Precision Oncology Satpathy et al., Microscaled Proteogenomic Methods for Precision Oncology 2 AbstractCancer proteogenomics integrates genomics, transcriptomics and mass spectrometry (MS)-based proteomics to gain insights into cancer biology and treatment efficacy. A proteogenomics approach was therefore developed for frozen core biopsies using tissue-sparing specimen processing with a "microscaled" proteomics workflow. For technical proof-of-principle, biopsies from ERBB2 positive breast cancers before and 48-72 hours after the first dose of neoadjuvant trastuzumabbased chemotherapy were analyzed. ERBB2 protein and phosphosite levels, as well as mTOR target phosphosites, were significantly more suppressed upon treatment in cases associated with pathological complete response, suggesting MS-based pharmacodynamics is achievable. Furthermore, integrated analyses indicated potential causes of treatment resistance including the absence of ERBB2 amplification (false-ERBB2 positive) and insufficient ERBB2 activity for therapeutic sensitivity despite ERBB2 amplification (pseudo-ERBB2 positive). Candidate resistance features in true-ERBB2+ cases, including androgen receptor signaling, mucin expression and an inactive immune microenvironment were observed. Thus, proteogenomic analysis of needle core biopsies is feasible and clinical utility should be investigated. enriched PDX (WHIM) models with ERBB2 protein expression. B. MUC1 immunohistochemistry (IHC) of WHIM8, WHIM35 and BCN1369.

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“…Recently it was shown that TNFα can induce MUC4 expression in HER2-positive breast and gastric cancer cells (38). Moreover, they observed a strong association between MUC4-positive tumors and a shorter DFS in patients receiving adjuvant trastuzumab-based treatment (39). We show here that [ 131 I]-2Rs15d binds four times higher to JIMT-1 compared to [ 131 I]-trastuzumab, while binding to trastuzumab-responsive BT474/M1 was similar for both compounds (Fig.…”

Section: Discussionmentioning

confidence: 99%

131I-labeled Anti-HER2 Camelid sdAb as a Theranostic Tool in Cancer Treatment

D’Huyvetter

Vos

Xavier

et al. 2017

Clinical Cancer Research

149

152

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Purpose Camelid single-domain antibody-fragments (sdAbs) have beneficial pharmacokinetic properties, and those targeted to HER2 can be used for imaging of HER2-overexpressing cancer. Labeled with a therapeutic radionuclide, they may be used for HER2-targeted therapy. Here we describe the generation of a 131I-labeled sdAb as a theranostic drug to treat HER2-overexpressing cancer. Experimental design Anti-HER2 sdAb 2Rs15d was labeled with 131I using [131I]SGMIB and evaluated in vitro. Biodistribution was evaluated in two HER2+ murine xenograft models by micro-SPECT/CT imaging and at necropsy, and under challenge with trastuzumab and pertuzumab. The therapeutic potential of [131I]SGMIB-2Rs15d was investigated in two HER2+ tumor mouse models. A single-dose toxicity study was performed in mice using unlabeled [127I]SGMIB-sdAb at 1.4mg/kg. The structure of the 2Rs15d-HER2 complex was determined by X-ray crystallography. Results [131I]SGMIB-2Rs15d bound specifically to HER2+ cells (KD=4.74±0.39nM). High and specific tumor uptake was observed in both BT474/M1 and SKOV-3 tumor xenografted mice and surpassed kidney levels by 3h. Extremely low uptake values were observed in other normal tissues at all time points. The crystal structure revealed that 2Rs15d recognizes HER2 Domain 1, consistent with the lack of competition with trastuzumab and pertuzumab observed in vivo. [131I]SGMIB-2Rs15d alone, or in combination with trastuzumab extended median survival significantly. No toxicity was observed after injecting [127I]SGMIB-2Rs15d. Conclusions These findings demonstrate the theranostic potential of [131I]SGMIB-2Rs15d. An initial scan using low radioactive [*I]SGMIB-2Rs15d allows patient selection and dosimetry calculations for subsequent therapeutic [131I]SGMIB-2Rs15d, and could thereby impact therapy outcome on HER2+ BC patients.

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TNFα-Induced Mucin 4 Expression Elicits Trastuzumab Resistance in HER2-Positive Breast Cancer

Cited by 92 publications

References 43 publications

Microscaled proteogenomic methods for precision oncology

Microscaled proteogenomic methods for precision oncology

Microscaled Proteogenomic Methods for Precision Oncology

131I-labeled Anti-HER2 Camelid sdAb as a Theranostic Tool in Cancer Treatment

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