Journal article
Transglutaminase-2 mediates acquisition of neratinib resistance in metastatic breast cancer
Molecular biomedicine, Vol.3(1), pp.19-19
06/22/2022
DOI: 10.1186/s43556-022-00079-y
PMCID: PMC9213622
PMID: 35729402
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.
Details
- Title: Subtitle
- Transglutaminase-2 mediates acquisition of neratinib resistance in metastatic breast cancer
- Creators
- Aparna Shinde - Purdue University West LafayetteEylem Kulkoyluoglu Cotul - West Lafayette, IN 47907 USAHao Chen - Purdue University West LafayetteAndrew Smith - Purdue University West LafayetteSarah Libring - Purdue University West LafayetteLuis Solorio - Purdue University West LafayetteMichael K. Wendt - Purdue University West Lafayette
- Resource Type
- Journal article
- Publication Details
- Molecular biomedicine, Vol.3(1), pp.19-19
- DOI
- 10.1186/s43556-022-00079-y
- PMID
- 35729402
- PMCID
- PMC9213622
- NLM abbreviation
- Mol Biomed
- ISSN
- 2662-8651
- eISSN
- 2662-8651
- Publisher
- Springer Nature Singapore
- Grant note
- ; RSG-CSM130259 / ; R01CA207751; R01CA232589; R00CA198929 / ; R21AA026675 / ;
- Language
- English
- Date published
- 06/22/2022
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984460325302771
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