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

Springer Science and Business Media LLC - Tập 3 Số 1 - 2022
Aparna Shinde1, Eylem Kulkoyluoglu-Cotul1, Hao Chen1, Andrew Smith1, Sarah Libring2, Luis Solorio2, Michael K. Wendt3
1Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907 USA
2Department of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA
3Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA

Tóm tắt

AbstractAcquisition 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.

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