A pathway-based approach for identifying biomarkers of tumor progression to trastuzumab-resistant breast cancer

Abstract

Although trastuzumab is a successful targeted therapy for breast cancer patients with tumors expressing HER2 (ERBB2), many patients eventually progress to drug resistance. Here, we identified subpathways differentially expressed between trastuzumab-resistant vs. -sensitive breast cancer cells, in conjunction with additional transcriptomic preclinical and clinical gene datasets, to rigorously identify overexpressed, resistance-associated genes. From this approach, we identified 32 genes reproducibly upregulated in trastuzumab resistance. 25 genes were upregulated in drug-resistant JIMT-1 cells, which also downregulated HER2 protein by >80% in the presence of trastuzumab. 24 genes were downregulated in trastuzumab-sensitive SKBR3 cells. Trastuzumab sensitivity was restored by siRNA knockdown of these genes in the resistant cells, and overexpression of 5 of the 25 genes was found in at least one of five refractory HER2 + breast cancer. In summary, our rigorous computational approach, followed by experimental validation, significantly implicate ATF4, CHEK2, ENAH, ICOSLG, and RAD51 as potential biomarkers of trastuzumab resistance. These results provide further proof-of-concept of our methodology for successfully identifying potential biomarkers and druggable signal pathways involved in tumor progression to drug resistance.

Phosphoproteins in extracellular vesicles as candidate markers for breast cancer

“…As a demonstration that PRM can be used to initially verify candidate phosphoproteins, we selected four phosphoproteins: Ral GTPase-activating protein subunit alpha-2 (RALGAPA2), cGMP-dependent protein kinase1 (PKG1), tight junction protein 2 (TJP2), and nuclear transcription factor, X box-binding protein 1 (NFX1). These four proteins showed significant phosphorylation up-regulation in patients with cancer, were previously reported as phosphoproteins, and have been implicated in multiple breast cancer studies (23)(24)(25)(26).…”

Recent Progress in HER2 Associated Breast Cancer

“…(Mohd Sharial et al, 2012;Takada et al, 2013;Xia et al, 2013;Kawajiri et al, 2015;Nam et al, 2015) has shown success in preclinical models. And the HER2 gene has been established as a valid biological marker for the treatment of breast cancer So far, Small Molecule Tyrosine Kinase Inhibitors of HER2 such as Trastuzumab, Pertuzumab, Lapatinib, Afatinib, AZD8931, AST-1306, AEE-788, CI-1033 (Canertinib), CP-724714, CUDC-101, TAK-285, AC-480 (BMS-599626), PF299804, PF299 (Dacomitinib), EKB-569 (Perlitinib) are on their way to clinical use or undergoing phase trials in aggressive breast cancer (Kumler et al, 2014;Schroeder et al, 2014), being explored for their potential to inhibit EGFR and HER2 tyrosine kinases.…”

“…However, a major limit of immunotherapy with trastuzumab is the development of drug resistance (Nahta, 2012;Brady et al, 2014;Nielsen et al, 2014;Rimawi et al, 2014;Zang et al, 2014;Nam et al, 2015). WenBai et al (2014) referred, trastuzumab resistance was DOI:http://dx.doi.org/10.7314/APJCP.2015.16.7.2591 Recent Progress in HER2 Associated Breast Cancer -a Review characterized by enhanced invasiveness of breast cancer cells with concomitant EMT and elevated TGF-b signaling (Bai et al, 2014).…”

“…Further, ATF4, CHEK2, ENAH, ICOSLG, and RAD51 has the potential of being biomarkers of trastuzumab resistance (Nam et al, 2015), and these may be validated by their up-regulation in refractory HER2 + breast cancer cells and tumors. Leading to inhibition of DNA repair, Sueta et al (2014) declared biomarkers such as PIK3CA mutation, and INPP4B were relevant to trastuzumab efficacy in HER2-positive breast cancer (Sueta et al, 2014).…”

“…Joyfully, about the mutant mechanism, researchers newly reported a case that a breast cancer patient harboring an activating EGFR mutation clinically benefiting from EGFR-targeted treatment (Ali et al, 2014). The immune way ADCC (Nahta, 2012) multiple mAbs HER2 internalization (Ben-Kasu et al, 2009) anti-HER2 vaccine Peptide-based/DNA-based/ anti-idiotypic (Cao et al, 2013;Tagliabue and Campiglio, 2014) Trastuzumab mitogenic signaling (Schroeder et al, 2014;Kawajiri et al, 2015) ADCC 188Re-labeled HYNIC-trastuzuma radioactivity dose-dependent fashion (Luo et al, 2015) 64Cu-DOTA-trastuzumab metastatic breast cancer (Mortimer et al, 2014) Trastuzumab resistance Upregulation of HER3 (Nahta, 2012;Brady et al, 2014;Rimawi et al, 2014;Zang et al, 2014;Nam et al, 2015) miRNAs (miRNA-21, miR-7, miR-200c) (Bai et al, 2014;Chen and Bourguignon, 2014;Huynh and Jones, 2014; H E R 2 c o p y n u m b e r / dimerization status Interaction between HER2 and other ERBB (Lee et al, 2015) autophagy (Yeh et al, 2014) Anthracyclines HER2/TOP2A (Fountzilas et al, 2012) S-222611 ERBB family dimmers (Spicer et al, 2015) NCT Increase pCR rates (Shinde et al, 2015) Flotillin reduction of ErbB2-ErbB3 (Asp and Pust, 2014) CC apoptosis/ proliferation (Khan et al, 2015) Taspase1 Cyclins E, A, and B (Dong et al, 2014) Combined therapy Trastuzumab, carboplatin, paclitaxel (Shinde et al, 2015) Trastuzumab, MK-2206 (Hudis et al, 2013) Trastuzumab, lapatinib (Rimawi et al, 2014;Scaltriti et al, 2014;Schroeder et al, 2014) lapatinib , BYL719 (Brady et al, 2014) AZD8931, paclitaxel (Kurata et al, 2014) Hsp90, laptinib ( …”