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

Aparna Shinde; Eylem Kulkoyluoglu Cotul; Hao Chen; Andrew Smith; Sarah Libring; Luis Solorio; Michael K Wendt

doi:10.1186/s43556-022-00079-y

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

Mol Biomed. 2022 Jun 22;3(1):19. doi: 10.1186/s43556-022-00079-y.

Authors

Aparna Shinde¹, Eylem Kulkoyluoglu Cotul¹, Hao Chen¹, Andrew Smith¹, Sarah Libring², Luis Solorio^{2

3}, Michael K Wendt^{4

5}

Affiliations

¹ Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA.
² Department of Biomedical Engineering, Purdue University, West Lafayette, IN, 47907, USA.
³ Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, 47907, USA.
⁴ Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA. mwendt@purdue.edu.
⁵ Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, 47907, USA. mwendt@purdue.edu.

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.

Keywords: Breast cancer; Drug resistance; HER2; IL-6; Metastasis.

Abstract

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