Overcoming acquired resistance to HSP90 inhibition by targeting JAK-STAT signalling in triple-negative breast cancer

Abstract

BackgroundDue 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.MethodsWe 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.ResultsAmong 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.ConclusionsAcquired 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.Electronic supplementary materialThe online version of this article (10.1186/s12885-019-5295-z) contains supplementary material, which is available to authorized users.

Heat Shock Proteins: Agents of Cancer Development and Therapeutic Targets in Anti-Cancer Therapy

“…Some of the clinical trials are completed (NCT01294202, NCT01685268, NCT00878423, NCT01246102), and others are recruiting more patients. Ganetespib, a second-generation synthetic HSP90 inhibitor that has exhibited promising antitumor effects with safety profiles, is being developed to treat metastasis-prone and drug-resistant thyroid, ovarian, breast, and non-small cell lung cancers, currently undergoing clinical trials [189][190][191][192]. Ganetespib effectively suppresses cancer progression by inducing G2/M cell cycle arrest through inhibition of RAS/RAF/ERK and PI3K/AKT/mTOR pathways and promoting caspase-3-mediated apoptosis [189,193].…”

“…Since GRP94 is responsible for the maturation and trafficking of proteins involved in cell signaling and motility, the treatment of GRP94-selective inhibitor 30 has shown potent anti-cancer activity in aggressive and metastatic cancers [209] (Table 7). [189][190][191][192] Papillary thyroid carcinoma NVP-AUY922-HSP90 inhibitor, inhibition of cell viability, induction of apoptosis, suppression of survivin [194] Gastric cancer an NSCLC NVP-AUY922, inhibition of tumor growth, angiogenesis, metastasis [210,211] Small cell lung cancer Co-administration of HSP90 inhibitor NVP-AUY922 and BCL-2 inhibitor ABT-737-induction of apoptosis, inhibition of ABT-737 drug resistance, downregulation of AKT and ERK [195], NCT01294202, NCT01685268, NCT00878423, NCT01246102…”

Heat shock protein 90α in thymic epithelial tumors and non-thymomatous myasthenia gravis

“…25 HSP27, HSP70 and HSP90, are overexpressed in several tumor entities 26−29 and their overexpression correlates with tumor growth, resistance to ChT, metastases and poor survival. 30,31 HSP90 is overexpressed in breast-, 28 colon- 29 and prostate cancer. 32 High HSP90 tumor expression reflects lower malignant potential in colon cancer.…”

Important players in carcinogenesis as potential targets in cancer therapy: an update

“…It includes four kinases, which after activation impact of the STAT molecules causing their translocation into the nuclei [16]. STAT, a family that gathers seven forms of proteins, is associated with cancer cell development, progression, metastasis, survival and resistance to treatment [17]. STAT3 and STAT5 factors seem to be the most important agents in light of cancer progression.…”