Pathway-focused proteomic signatures in HER2-overexpressing breast cancer with a basal-like phenotype: New insights into de novo resistance to trastuzumab (Herceptin)

Oliveras‐Ferraros, Cristina; Vázquez-Martín, Alejandro; Martín-Castillo, Begoña; Pérez-Martínez, Maria Carmen; Cufí, Sílvia; Barco, Sonia Del; Bernadó, Luis; Brunet, Joan; López-Bonet, Eugeni; Menéndez, Javier A.

doi:10.3892/ijo_00000716

Cited by 33 publications

(5 citation statements)

References 36 publications

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“…IGF1R and IR are frequently expressed at high levels in various malignancies such as breast cancer [ 40 , 41 , 42 ], colorectal cancer [ 43 , 44 ], and NSCLC [ 45 , 46 ]. Dysregulation of IGF1R/IR axis acts as an oncogenic signal in initial tumorigenesis as well as mediating resistance to targeted therapies [ 47 , 48 ]. The IGF2/IGF1R/IR axis mediates adaptive resistance to erlotinib by undergoing an IGF1R/IR phenotypic switch in cholangiocarcinoma [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

IGF1R/IR Mediates Resistance to BRAF and MEK Inhibitors in BRAF-Mutant Melanoma

Patel

Mishra

Yacoub

et al. 2021

Cancers

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The use of BRAF and MEK inhibitors for patients with BRAF-mutant melanoma is limited as patients relapse on treatment as quickly as 6 months due to acquired resistance. We generated trametinib and dabrafenib resistant melanoma (TDR) cell lines to the MEK and BRAF inhibitors, respectively. TDR cells exhibited increased viability and maintenance of downstream p-ERK and p-Akt as compared to parental cells. Receptor tyrosine kinase arrays revealed an increase in p-IGF1R and p-IR in the drug resistant cells versus drug sensitive cells. RNA-sequencing analysis identified IGF1R and INSR upregulated in resistant cell lines compared to parental cells. Analysis of TCGA PanCancer Atlas (skin cutaneous melanoma) showed that patients with a BRAF mutation and high levels of IGF1R and INSR had a worse overall survival. BMS-754807, an IGF1R/IR inhibitor, suppressed cell proliferation along with inhibition of intracellular p-Akt in TDR cells. Dual inhibition of IGF1R and INSR using siRNA reduced cell proliferation. The combination of dabrafenib, trametinib, and BMS-754807 treatment reduced in vivo xenograft tumor growth. Examining the role of IGF1R and IR in mediating resistance to BRAF and MEK inhibitors will expand possible treatment options to aid in long-term success for BRAF-mutant melanoma patients.

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Section: Discussionmentioning

confidence: 99%

IGF1R/IR Mediates Resistance to BRAF and MEK Inhibitors in BRAF-Mutant Melanoma

Patel

Mishra

Yacoub

et al. 2021

Cancers

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“…We and others recently observed that resistance to Trastuzumab leads Her2+ breast cancer cells to display the phenotypes of TNBC through the activation of NF-κB. 10 , 11 TNBC cells are known to harbor constitutive activation of NF-κB, 12 , 13 which is implicated in poor prognosis for TNBC patients.…”

Section: Introductionmentioning

confidence: 99%

Disabling the Nuclear Translocalization of RelA/NF-κB by a Small Molecule Inhibits Triple-Negative Breast Cancer Growth

Kanzaki¹,

Chatterjee²,

Ariani³

et al. 2021

BCTT

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Introduction: Constitutive activation of NF-κB has been implicated as being contributive to cancer cell growth, drug resistance, and tumor recurrence in many cancers including breast cancer. Activation of NF-κB leads to nuclear translocation of RelA, a critical component of the NF-κB transcription factor complex, which subsequently binds to specific DNA sites and activates a multitude of genes involved in diverse cell functions. Studies show that triplenegative breast cancer (TNBC) cells possess constitutively active NF-κB and concomitantly have higher levels of nuclear localization of RelA than cytoplasmic RelA. This feature is considered to be associated with the response to chemotherapy. However, currently, there is no specific inhibitor to block nuclear translocation of RelA. Methods: A structure-based approach was used to develop a small-molecule inhibitor of RelA nuclear translocation. The interaction between this molecule and RelA was verified biophysically through isothermal titration calorimetry and microscale thermophoresis. TNBC cell lines MDA-MB-231 and MDA-MB-468 and a human TNBC xenograft model were used to verify in vitro and in vivo efficacy of the small molecule, respectively. Results: We found that the small molecule, CRL1101, bound specifically to RelA as indicated by the biophysical assays. Further, CRL1101 blocked RelA nuclear translocation in breast cancer cells in vitro, and markedly reduced breast tumor growth in a triple-negative breast cancer xenograft model. Conclusion:Our study demonstrates that CRL1101 may lead to new NF-κB-targeted therapeutics for TNBC. Further, blocking of nuclear translocation of shuttling transcription factors may be a useful general strategy in cancer drug development.

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“…Unfortunately, little is known about the analysis tools that can be applied to explore changes in the expression of autophagy genes or about the functional importance of putative candidate genes emerging from autophagy-dedicated transcriptome studies. In this context, we first assessed the utility of an autophagy-focused polymerase chain reaction (PCR) array to identify novel autophagy-specific gene biomarkers for intrinsic (primary) resistance to trastuzumab in HER2 gene-amplified breast cancer cells that naturally exhibit bona fide primary resistance to HER-targeted therapies [ 12 , 13 , 17 , 53 - 55 ]. Second, using molecular biology approaches we unambiguously validated whether the autophagy genes differentially expressed in trastuzumab-refractory breast carcinoma cells functionally predicted the primary response to the growth-inhibitory and anti-tumoral effects of trastuzumab.…”

Section: Introductionmentioning

confidence: 99%

Autophagy-related gene 12 (ATG12) is a novel determinant of primary resistance to HER2-targeted therapies: Utility of transcriptome analysis of the autophagy interactome to guide breast cancer treatment

et al. 2012

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The autophagic process, which can facilitate breast cancer resistance to endocrine, cytotoxic, and molecularly targeted agents, is mainly regulated at the post-translational level. Although recent studies have suggested a possible transcriptome regulation of the autophagic genes, little is known about either the analysis tools that can be applied or the functional importance of putative candidate genes emerging from autophagy-dedicated transcriptome studies. In this context, we evaluated whether the constitutive activation of the autophagy machinery, as revealed by a transcriptome analysis using an autophagy-focused polymerase chain reaction (PCR) array, might allow for the identification of novel autophagy-specific biomarkers for intrinsic (primary) resistance to HER2-targeted therapies. Quantitative real-time PCR (qRT-PCR)-based profiling of 84 genes involved in autophagy revealed that, when compared to trastuzumab-sensitive SKBR3 cells, the positive regulator of autophagic vesicle formation ATG12 (autophagy-related gene 12) was the most differentially up-regulated gene in JIMT1 cells, a model of intrinsic cross-resistance to trastuzumab and other HER1/2-targeting drugs. An analysis of the transcriptional status of ATG12 in > 50 breast cancer cell lines suggested that the ATG12 transcript is commonly upregulated in trastuzumab-unresponsive HER2-overexpressing breast cancer cells. A lentiviral-delivered small hairpin RNA stable knockdown of the ATG12 gene fully suppressed the refractoriness of JIMT1 cells to trastuzumab, erlotinib, gefitinib, and lapatinib in vitro. ATG12 silencing significantly reduced JIMT1 tumor growth induced by subcutaneous injection in nude mice. Remarkably, the outgrowth of trastuzumab-unresponsive tumors was prevented completely when trastuzumab treatment was administered in an ATG12-silenced genetic background. We demonstrate for the first time the usefulness of low-density, autophagy-dedicated qRT-PCR-based platforms for monitoring primary resistance to HER2-targeted therapies by transcriptionally screening the autophagy interactome. The degree of predictive accuracy warrants further investigation in the clinical situation.

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Pathway-focused proteomic signatures in HER2-overexpressing breast cancer with a basal-like phenotype: New insights into de novo resistance to trastuzumab (Herceptin)

Cited by 33 publications

References 36 publications

IGF1R/IR Mediates Resistance to BRAF and MEK Inhibitors in BRAF-Mutant Melanoma

IGF1R/IR Mediates Resistance to BRAF and MEK Inhibitors in BRAF-Mutant Melanoma

Disabling the Nuclear Translocalization of RelA/NF-κB by a Small Molecule Inhibits Triple-Negative Breast Cancer Growth

Autophagy-related gene 12 (ATG12) is a novel determinant of primary resistance to HER2-targeted therapies: Utility of transcriptome analysis of the autophagy interactome to guide breast cancer treatment

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