Transglutaminase-2 mediates acquisition of neratinib resistance in metastatic breast cancer

Abstract

Acquisition of resistance to targeted therapies remains a major clinical obstacle for the HER2+ subtype of breast cancer. Using an isogeneic progression series of HER2+ breast cancer metastasis we demonstrate that metastatic cells have an increased capacity to acquire resistance to the covalent, pan-ErbB inhibitor, neratinib. RNA sequencing analyses comparing parental and metastatic cells identified upregulation of transglutaminase 2 (TG2). Genetic depletion and overexpression approaches established that TG2 is both necessary and sufficient for acquisition of neratinib resistance. Mechanistically, we describe a pathway in which TG2-mediates activation of NF-κB signaling leading to upregulation of IL-6 in metastatic cells. This autocrine expression of IL-6 functions to maintain enhanced levels of TG2 via JAK:STAT3 signaling. This drug persistence feedback loop can be interrupted through the use of the JAK1/2 inhibitor ruxolitinib. In vivo application of ruxolitinib had no effect on tumor growth under non-treated conditions, but effectively prevented acquisition of resistance, leading to tumor regression upon coadministration with neratinib. Overall, our studies reveal a mechanism in metastatic breast cancer cells that predisposes them to acquisition of resistance to ErbB-targeted therapeutics. Clinically, immediate application of ruxolitinib could prevent acquisition of resistance and improve patient responses to HER2-targeted therapies.

Docosahexaenoic Acid, a Key Compound for Enhancing Sensitization to Drug in Doxorubicin-Resistant MCF-7 Cell Line

“…In our study, we found that doxorubicin accumulation was enhanced in both doxorubicin sensitive and resistant MCF-7 cells when treated with DHA. Downregulation of P-glycoprotein (P-gp) and Transglutaminase 2 (TG2) has been identified as a potential mechanism to sensitize drug-resistant breast cancer cells to chemotherapy [ 66 ]. These two proteins are known to be overexpressed in many drug-resistant cancer cells, leading to increased drug efflux and decreased drug accumulation, thereby reducing the effectiveness of chemotherapy [ 66 , 67 , 68 , 69 , 70 ].…”

“…Downregulation of P-glycoprotein (P-gp) and Transglutaminase 2 (TG2) has been identified as a potential mechanism to sensitize drug-resistant breast cancer cells to chemotherapy [ 66 ]. These two proteins are known to be overexpressed in many drug-resistant cancer cells, leading to increased drug efflux and decreased drug accumulation, thereby reducing the effectiveness of chemotherapy [ 66 , 67 , 68 , 69 , 70 ]. One mechanism by which drug accumulation can be enhanced is by inhibiting drug efflux transporters, which are proteins that pump drugs out of cancer cells and decrease drug accumulation [ 70 , 71 , 72 , 73 ].…”

The Role of Transglutaminase 2 in Cancer: An Update

“…Despite significant efforts in recent decades, the mechanism driving tumorigenesis and progression remains elusive [ 64 ]. Since 1996, it has been postulated that TG2 plays a role in breast cancer [ 26 ], demonstrating its involvement in fostering the EMT [ 48 ], advancing metastatic progression [ 65 , 66 , 67 ], and contributing to drug resistance [ 36 , 37 , 38 ]; see Figure 6 .…”

“…A role of TG2 in promoting resistance to common anti-cancer drugs, including doxorubicin [ 36 ], neratinib [ 37 ], and PD-L1 inhibitors [ 38 ], has been shown. For example, TG2 mediates NF-κB activation, interleukin-6 (IL-6) upregulation, and Janus kinase/ signal transducer and activator of transcription 3 (JAK/STAT3) induction, thus promoting tumor progression, the acquisition of a stem-like phenotype, and neratinib resistance [ 37 ]. Another study suggests that TG2 could be considered a valuable predictive marker for identifying patients with triple-negative breast cancer who may be resistant to PD-L1 inhibitors.…”

Metabolic characterisation of transglutaminase 2 inhibitor effects in breast cancer cell lines

“…The present study focuses on the emerging relevance of Transglutaminase 2 (TG2) in breast cancer (BrCa) [1]. This enzyme plays a role in inflammation [2][3][4], mediates the onset of drug resistance [5][6][7], and controls epithelial-to-mesenchymal transition (EMT), sustaining the motility and invasiveness of BrCa cells [8][9][10]. However, how TG2 intervenes in these pathological processes is complex, depending primarily on its dual action, derived from its ability to act both as a G protein and to catalyse transamidation reactions [11].…”