An integrated stress response via PKR suppresses HER2+ cancers and improves trastuzumab therapy

Abstract

Trastuzumab is integral to HER2+ cancer treatment, but its therapeutic index is narrowed by the development of resistance. Phosphorylation of the translation initiation factor eIF2α (eIF2α-P) is the nodal point of the integrated stress response, which promotes survival or death in a context-dependent manner. Here, we show an anti-tumor function of the protein kinase PKR and its substrate eIF2α in a mouse HER2+ breast cancer model. The anti-tumor function depends on the transcription factor ATF4, which upregulates the CDK inhibitor P21 CIP1 and activates JNK1/2. The PKR/eIF2α-P arm is induced by Trastuzumab in sensitive but not resistant HER2+ breast tumors. Also, eIF2α-P stimulation by the phosphatase inhibitor SAL003 substantially increases Trastuzumab potency in resistant HER2+ breast and gastric tumors. Increased eIF2α-P prognosticates a better response of HER2+ metastatic breast cancer patients to Trastuzumab therapy. Hence, the PKR/eIF2α-P arm antagonizes HER2 tumorigenesis whereas its pharmacological stimulation improves the efficacy of Trastuzumab therapy.

Impact of Eukaryotic Translation Initiation Factors on Breast Cancer: Still Much to Investigate

“…All of the above are referred to as the integrated stress response (ISR) ( Figure 1). Increased phospho-eIF2α not only leads to the mRNA translation initiation inhibition, but also facilitates the translation of selected mRNAs, which encode proteins participated in the process of adaptation to stress [25].…”

“…Trastuzumab can induce the PKR/eIF2α-P and its downstream anti-tumor pathways, in sensitive but not resistant HER2+ BC. For the overall survival rate of HER2+ BC patients treated with Trastuzumab-based chemotherapy, an increased level of eIF2α-P can act as an independent positive prognostic marker [25]. As the stimulation of eIF2α phosphorylation by the phosphatase inhibitor (SAL003) can improve the efficacy of Trastuzumab, it might be a potential biomarker for its effectiveness [25] (Figure 1).…”

“…Environmental stress and PI3K-AKT inhibitors are able to down-regulate AKT-p-T799 and to activate PERK [13]. SAL003 can improve the efficiency of Trastuzumab, and Trastuzumab can stimulate PKR [25]. eIF2α-p leads to an inhibition of the translation initiation [26] and can inhibit HER2+.…”

Crosstalks between inflammasome and autophagy in cancer

“…The drug plitidepsin, which inhibits the interaction between eEF1A2 and PKR, has been shown to induce cancer cell death by activating the extrinsic apoptosis pathway [ 67 ]. In addition, PKR/eIF2α-P axis inhibition showed anti-tumor effects against HER2-positive breast cancer and gastric cancer [ 68 ]. Moreover, the eIF2α-phosphatase inhibitor SAL003 potentiated the anti-tumor effects of trastuzumab in HER2-positive tumor cells [ 68 ].…”

The role of autophagy in the cytotoxicity induced by trastuzumab emtansine (T-DM1) in HER2-positive breast cancer cells

“…Trastuzumab, a humanized monoclonal antibody which targets HER2 extracellular domain, has been approved since 1998 as the prior neoadjuvant treatment for HER2-overexpressed metastatic breast cancer (Romond et al 2005;Slamon et al 2011). In spite of the improvements in outcomes of HER2-targeted therapy, approximately a quarter of patients who have received HER2-targeted therapy plus neoadjuvant chemotherapy are then found to have residual invasive breast cancer at surgery (Darini et al 2019;Zhang et al 2011). These limitations raise the necessity for achieving better understanding of biological mechanisms of these agents and developing better approaches for the treatment of HER2-overexpressed breast cancer.…”