1. Overcoming acquired resistance to HSP90 inhibition by targeting JAK-STAT signalling in triple-negative breast cancer.
- Author
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Mumin NH, Drobnitzky N, Patel A, Lourenco LM, Cahill FF, Jiang Y, Kong A, and Ryan AJ
- Subjects
- Apoptosis drug effects, Cell Line, Tumor, Drug Resistance, Neoplasm genetics, Drug Synergism, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Interleukin-6 metabolism, Signal Transduction genetics, Small Molecule Libraries pharmacology, Triazoles pharmacology, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms metabolism, Drug Resistance, Neoplasm drug effects, HSP90 Heat-Shock Proteins antagonists & inhibitors, Janus Kinase 2 antagonists & inhibitors, Signal Transduction drug effects, Triple Negative Breast Neoplasms pathology
- Abstract
Background: Due to the lack of effective therapies and poor prognosis in TNBC (triple-negative breast cancer) patients, there is a strong need to develop effective novel targeted therapies for this subtype of breast cancer. Inhibition of heat shock protein 90 (HSP90), a conserved molecular chaperone that is involved in the regulation of oncogenic client proteins, has shown to be a promising therapeutic approach for TNBC. However, both intrinsic and acquired resistance to HSP90 inhibitors (HSP90i) limits their effectiveness in cancer patients., Methods: We developed models of acquired resistance to HSP90i by prolonged exposure of TNBC cells to HSP90i (ganetespib) in vitro. Whole transcriptome profiling and a 328-compound bioactive small molecule screen were performed on these cells to identify the molecular basis of acquired resistance to HSP90i and potential therapeutic approaches to overcome resistance., Results: Among a panel of seven TNBC cell lines, the most sensitive cell line (Hs578T) to HSP90i was selected as an in vitro model to investigate acquired resistance to HSP90i. Two independent HSP90i-resistant clones were successfully isolated which both showed absence of client proteins degradation, apoptosis induction and G2/M cell cycle arrest after treatment with HSP90i. Gene expression profiling and pathway enrichment analysis demonstrate significant activation of the survival JAK-STAT signalling pathway in both HSP90i-resistant clones, possibly through IL6 autocrine signalling. A bioactive small molecule screen also demonstrated that the HSP90i-resistant clones showed selective sensitivity to JAK2 inhibition. Inhibition of JAK and HSP90 caused higher induction of apoptosis, despite prior acquired resistance to HSP90i., Conclusions: Acquired resistance to HSP90i in TNBC cells is associated with an upregulated JAK-STAT signalling pathway. A combined inhibition of the JAK-STAT signalling pathway and HSP90 could overcome this resistance. The benefits of the combined therapy could be explored further for the development of effective targeted therapy in TNBC patients.
- Published
- 2019
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