Cancer cells harboring MET gene amplification activate alternative signaling pathways to escape MET inhibition but remain sensitive to Hsp90 inhibitors

Wang, Suiquan; Pashtan, Itai; Tsutsumi, Shinji; Xu, Wanping; Neckers, Len

doi:10.4161/cc.8.13.8861

Cited by 35 publications

(35 citation statements)

References 33 publications

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“…In this setting, the relevant biology may relate to the ability of an Hsp90 inhibitor to block oncogenic switching to signaling via other receptor tyrosine kinases [48][49][50]. The oncogenic switch has been shown to be induced as a resistance mechanism to TKIs, but most of the alternative kinases in cancer cells are Hsp90 clients that are sensitive to Hsp90 inhibition.…”

Section: Resultsmentioning

confidence: 99%

Update on Hsp90 Inhibitors in Clinical Trial

Kim¹,

Alarcon²,

Lee³

et al. 2009

CTMC

265

244

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Twenty-five years ago the first small molecule inhibitors of Hsp90 were identified. In the intervening years there has been dramatic progress in basic scientific understanding of the Hsp90 chaperone machinery and in the role of Hsp90 in malignancy. The first-in-class Hsp90 inhibitor 17-AAG entered into Phase I clinical trials in 1999. There are now 13 Hsp90 inhibitors in clinical trial, representing multiple drug classes, and hundreds of patients have been treated in adult oncology and pediatric oncology trials. This review will provide an overview of the clinical trial results thus far. In addition, pivotal issues in further development of Hsp90 inhibitors as anticancer drugs will be discussed.

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Section: Resultsmentioning

confidence: 99%

Update on Hsp90 Inhibitors in Clinical Trial

Kim¹,

Alarcon²,

Lee³

et al. 2009

CTMC

265

244

View full text Add to dashboard Cite

show abstract

“…For example, HSP90 inhibition suppresses EGFR activity and downstream signaling in erlotinib-resistant EGFR/T790M-expressing cells (42), and suppresses ALK activity and signaling in cells expressing crizotinib-resistant EML4-ALK/L1196M (43). Similarly, targeting HSP90 prevents escape of ErbB2-driven breast cancer cells from chronic ErbB inhibition and escape of MET-amplified tumor cells from MET-TKI (44,45).…”

Section: Discussionmentioning

confidence: 99%

The HSP90 Inhibitor Ganetespib Synergizes with the MET Kinase Inhibitor Crizotinib in both Crizotinib-Sensitive and -Resistant MET-Driven Tumor Models

et al. 2013

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The proto-oncogene MET is aberrantly activated via overexpression or mutation in numerous cancers, making it a prime anticancer molecular target. However, the clinical success of MET-directed tyrosine kinase inhibitors (TKI) has been limited due, in part, to mutations in the MET kinase domain that confer therapeutic resistance. Circumventing this problem remains a key challenge to improving durable responses in patients receiving METtargeted therapy. MET is an HSP90-dependent kinase, and in this report we show that HSP90 preferentially interacts with and stabilizes activated MET, regardless of whether the activation is ligand-dependent or is a consequence of kinase domain mutation. In contrast, many MET-TKI show a preference for the inactive form of the kinase, and activating mutations in MET can confer resistance. Combining the HSP90 inhibitor ganetespib with the MET-TKI crizotinib achieves synergistic inhibition of MET, its downstream signaling pathways, and tumor growth in both TKI-sensitive and -resistant MET-driven tumor models. These data suggest that inclusion of an HSP90 inhibitor can partially restore TKI sensitivity to previously resistant MET mutants, and they provide the foundation for clinical evaluation of this therapeutic combination in patients with MET-driven cancers. Cancer Res; 73(23); 7022-33. Ó2013 AACR.

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“…MET, a receptor for hepatoctye growth factor/scatter factor (HGF/SF) has been previously shown to play an important role in cancer invasion and metastasis [32]. As c-MET is a client of Hsp90, it is destabilised by the Hsp90 inhibitor, 17-AAG, which blocks reactivation of downstream signalling pathways (Akt Erk and/or STAT3) and EGFR family members [33]. Webb et al [34] showed that geldanamycin (GA) down regulates MET expression at nanamolar concentrations, thus inhibiting HGF/SF-mediated cell motility and invasion.…”

Section: Discussionmentioning

confidence: 99%

RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation

et al. 2011

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Keywords:Hop/STIP1/STI1 (Hsp70/Hsp90-organising protein) Pancreatic cancer Immunohistochemistry In vitro invasion MMP-2 a b s t r a c tWe previously identified Hop as over expressed in invasive pancreatic cancer cell lines and malignant tissues of pancreatic cancer patients, suggesting an important role for Hop in the biology of invasive pancreatic cancer. Hop is a co-chaperone protein that binds to both Hsp70/Hsp90. We hypothesised that by targeting Hop, signalling pathways modulating invasion and client protein stabilisation involving Hsp90-dependent complexes may be altered.In this study, we show that Hop knockdown by small interfering (si)RNA reduces the invasion of pancreatic cancer cells, resulting in decreased expression of the downstream target gene, matrix metalloproteinases-2 (MMP-2). Hop in conditioned media co-immunoprecipitates with MMP-2, implicating a possible extracellular function for Hop. Knockdown of Hop expression also reduced expression levels of Hsp90 client proteins, HER2, Bcr-Abl, c-MET and v-Src. Furthermore, Hop is strongly expressed in high grade PanINs compared to lower PanIN grades, displaying differential localisation in invasive ductal pancreatic cancer, indicating that the localisation of Hop is an important factor in pancreatic tumours.Our data suggests that the attenuation of Hop expression inactivates key signal transduction proteins which may decrease the invasiveness of pancreatic cancer cells possibly through the modulation of Hsp90 activity. Therefore, targeting Hop in pancreatic cancer may constitute a viable strategy for targeted cancer therapy.

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Cancer cells harboring MET gene amplification activate alternative signaling pathways to escape MET inhibition but remain sensitive to Hsp90 inhibitors

Cited by 35 publications

References 33 publications

Update on Hsp90 Inhibitors in Clinical Trial

Update on Hsp90 Inhibitors in Clinical Trial

The HSP90 Inhibitor Ganetespib Synergizes with the MET Kinase Inhibitor Crizotinib in both Crizotinib-Sensitive and -Resistant MET-Driven Tumor Models

RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation

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