HER2-mTOR signaling–driven breast cancer cells require ER-associated degradation to survive

Abstract

Targeting non-oncogenic vulnerabilities may provide additional therapeutic approaches in tumors that are resistant to oncogene-targeted therapy. Using a computational pathway-based approach, we interrogated clinical breast cancer genomic data sets for candidate non-oncogenic vulnerabilities in breast cancers that have genomic amplification of ERBB2, which encodes human epidermal growth factor 2 (HER2). HER2-positive (HER2(+)) breast cancers showed increased expression of genes encoding proteins in the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. Genetic ablation or pharmacological inhibition of ERAD led to irrecoverable ER stress and selectively killed HER2(+) breast cancer cells. Cell death caused by ERAD inhibition partially depended on increased HER2-mTOR signaling, which imposed an increased proteotoxic burden on the ER. Cell death in response to ER stress required the IRE1α-JNK pathway, which was selectively suppressed in HER2(+) breast cancers by phosphatases that inactivate JNK. Accordingly, the cytotoxicity of inhibiting ERAD as well as JNK phosphatases was synergistic in HER2(+) but not in HER2-negative breast cancer cells. Therefore, our study suggests that reactivation of oncogene-induced stress by targeting stress-adaptive pathways may be a beneficial approach for therapy-resistant breast cancers.

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“…The research efforts in cancer genomics have mainly www.impactjournals.com/oncotarget focused on the driver genes, and less attention has been given to the onco-passengers that have undergone similar CNVs as the driver genes. Previously, we showed that the pathway expression landscape of breast cancers with ERBB2 amplifications is largely driven by gene CNVs [16]. In this study, we confirm this finding at a broader scale, and show that onco-passenger gene expression has a significant contribution to the tumor transcriptomes.…”

Disulfide bond disrupting agents activate the unfolded protein response in EGFR- and HER2-positive breast tumor cells

“…Since disulfide bond formation occurs in the Endoplasmic Reticulum (ER), and HER2+ breast cancers are particularly sensitive to DDAs [33] and ER stress/ERAD [25], we examined whether DDAs (such as RBF3) activate the Unfolded Protein Response (UPR). In the DDA-sensitive MDA-MB-468, BT474, and SKBR3 lines, DDAs activated ER stress as indicated by GRP78 upregulation (Figure 1A).…”

“…The sensitivity of HER2+ breast cancer cells to ERAD inhibition depends on continued protein synthesis [25]. The protein synthesis inhibitors cycloheximide (CHX) and puromycin function by interfering with the translocation step in protein synthesis and by inducing premature chain termination during translation, respectively.…”

“…HER2-positive breast cancers are addicted to Endoplasmic Reticulum-Associated protein Destruction (ERAD) [25]. This may result from the reliance of these cancers on HER-family proteins and the fact that HER-family members EGFR, HER2, HER3, and HER4 share conserved extracellular cysteine-rich repeats that form numerous disulfide bonds that on overexpression may present a burden to the protein folding machinery.…”

Inactive rhomboid proteins: New mechanisms with implications in health and disease

“…Some evidence in favor of this comes from a study showing that tumor lines positive for the oncogene HER2 upregulate the ERAD machinery [72]. Crucially, cells unresponsive to HER2-targeting drugs are sensitive to ERAD inhibition, displaying the ERAD 'addiction' alluded to above.…”