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Emergence of resistance to tyrosine kinase inhibitors in non-small cell lung cancer can be delayed by an upfront combination with the HSP90 inhibitor onalespib

ABSTRACT: Emergence of resistance to tyrosine kinase inhibitors in non-small cell lung cancer can be delayed by an upfront combination with the HSP90 inhibitor onalespib

PROVIDER: PRJEB14706 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR1518932_1.fastq.gz	Fastqsanger.gz
	ERR1518932_2.fastq.gz	Fastqsanger.gz
	ERR1518933_1.fastq.gz	Fastqsanger.gz
	ERR1518933_2.fastq.gz	Fastqsanger.gz
	ERR1518934_1.fastq.gz	Fastqsanger.gz

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Emergence of resistance to tyrosine kinase inhibitors in non-small-cell lung cancer can be delayed by an upfront combination with the HSP90 inhibitor onalespib.

Project description:BackgroundTyrosine kinase inhibitors, such as crizotinib and erlotinib, are widely used to treat non-small-cell lung cancer, but after initial response, relapse is common because of the emergence of resistance through multiple mechanisms. Here, we investigated whether a frontline combination with an HSP90 inhibitor could delay the emergence of resistance to these inhibitors in preclinical lung cancer models.MethodsThe HSP90 inhibitor, onalespib, was combined with either crizotinib or erlotinib in ALK- or EGFR-activated xenograft models respectively (H2228, HCC827).ResultsIn both models, after initial response to the monotherapy kinase inhibitors, tumour relapse was observed. In contrast, tumour growth remained inhibited when treated with an onalespib/kinase inhibitor combination. Analysis of H2228 tumours, which had relapsed on crizotinib monotherapy, identified a number of clinically relevant crizotinib resistance mechanisms, suggesting that HSP90 inhibitor treatment was capable of suppressing multiple mechanisms of resistance. Resistant cell lines, derived from these tumours, retained sensitivity to onalespib (proliferation and signalling pathways were inhibited), indicating that, despite their resistance to crizotinib, they were still sensitive to HSP90 inhibition.ConclusionsTogether, these preclinical data suggest that frontline combination with an HSP90 inhibitor may be a method for delaying the emergence of resistance to targeted therapies.

| S-EPMC5117788 | biostudies-literature

Wee1 Inhibition sensitizes prostate cancer cells to Hsp90 inhibitor to activate the intrinsic apoptotic pathway

Project description:Heat shock protein 90 (Hsp90) is an essential evolutionarily conserved molecular chaperone in eukaryotes. Cancer cells rely on Hsp90 to chaperone activated oncoproteins, and its involvement in numerous signaling pathways makes it an attractive target for drug development. Surprisingly, however, the impact of Hsp90 inhibitors on cancer cells is most commonly cytostatic, and efforts to enhance the anti-tumor activity of Hsp90 inhibitors in the clinic remain a significant challenge. In this study, we show that dual inhibition of Wee1 tyrosine kinase and Hsp90 causes prostate cancer cells to undergo apoptosis. Gene-expression profiling revealed that induction of the intrinsic apoptotic pathway by this drug combination coincided with transcriptional down-regulation of Survivin and Wee1, an outcome not seen in cells treated separately with either agent. At the translational level, expression of these two proteins as well as activated Akt was completely abrogated. Similar results were obtained in prostate cancer xenografts. These data establish a novel therapeutic strategy to enhance the efficacy of Hsp90 inhibitors in prostate cancer, and they provide a mechanistic rationale for stimulating the pro-apoptotic activity of Hsp90 inhibitors. In order to explore the mechanism underlying the enhanced cell death caused by Wee1 inhibitorII and 17-AAG combination, we performed microarray analysis using PC3 cells treated with Wee1 inhibitorII alone, 17-AAG alone, or the two drugs in combination.

2013-01-10 | GSE38972 | GEO

Wee1 Inhibition sensitizes prostate cancer cells to Hsp90 inhibitor to activate the intrinsic apoptotic pathway

2013-01-10 | E-GEOD-38972 | biostudies-arrayexpress

Molecular determinants of Hsp90 recognition of Src kinase revealed by deep mutational scanning

Project description:Protein tyrosine kinases are involved in regulating growth and proliferation in cells and are often hyperactive in cancerous tissue. Tyrosine kinase inhibitors have been used to limit hyperactivity but become ineffective due to the appearance of resistance mutations. A common trait of hyperactive protein kinases is its strict client relationship with molecular chaperone Hsp90. However, the mechanism behind Hsp90 client kinase recognition is poorly understood. Here we measure the functional effect of thousands of single amino acid variants in the Src kinase domain to identify positions invovled in Hsp90 client recognition.

2023-05-22 | GSE218190 | GEO

Bioligical pathways of Hsp90 inhibitors in adult T cell leukemia cell lines

Project description:Heat shock protein 90 (Hsp90) is essential for the stability and the function of many client proteins, such as ERB2, C-RAF, CDK4, HIF-1 aplha and AKT. Recent reports demonstrated that inhibition of Hsp90 modulates multiple functions required for survival of human cancer, such as myeloma (Mitsiades et al, Blood:107, 1092, 2006), The aim of this study is evaluate the effect of Hsp90 inhibition, and to identify molecular pathways responsible for anti-proliferative effect on ATL cells. For Hsp90 inhibition, Geldanamycin derivates, 17AAG (17-allylamino -17-demethoxygeldanamycin) and 17DMAG (17-(dimethylaminoethylamino) 17-demethoxygeldanamycin) were used in this study. Interleukin 2-independent ATL cell lines (MT-2 and MT-4) and an interleukin 2-dependent ATL cell line (TaY-E10) were incubated, with or without Hsp90 inhibitors.

2009-05-27 | GSE12287 | GEO

Identification of targets regulated by MLL1 in response to HSP90 inhibitors

Project description:MLL1 WT or KO MEF with and without HSP90 inhibitor treatment

2014-04-15 | GSE56492 | GEO

Identification of targets regulated by HSF1 in response to HSP90 inhibitors

Project description:A375 cells with inducible knockdown HSF1 with and without HSP90 inhibitor treatment

2013-03-06 | GSE44867 | GEO

Cdc37 and Hsp90 tyrosine phosphorylation modulate the kinase chaperone cycle

Project description:Cdc37 is a core cochaperone of the Hsp90 machinery. It is involved in an early stage of the chaperone cycle to activate nascent forms of protein kinases as well as to stabilize mature forms of a subset of protein kinases. Overall, the chaperone cycle is quite complex and involves several steps. Progression, through these steps is regulated by the incorporation of several other cochaperones, ATP hydrolysis and posttranslational modifications on both Cdc37 and Hsp90. We show that phosphorylation of Cdc37 at Y298 by Yes kinase results in partial unfolding of its C-terminal domain, without affecting its ability to form binary or ternary complexes with kinases and Hsp90. Unfolding, unmasks a phosphopeptide sequence that exhibits high affinity for SH2 domains of non-receptor tyrosine kinases (nRTKs), resulting in their recruitment in the chaperone complex. In turn, the high local concentration of nRTKs potentiates Hsp90 phosphorylation at Y197, which results in dissociation of this early kinase-recruitment complex

2018-01-22 | PXD008375 | Pride

Identification of targets regulated by MLL1 in response to HSP90 inhibitors

Project description:MLL1 WT or KO MEF with and without HSP90 inhibitor treatment MEF cells were seeded in 6-well plates for 3d with 100ng/ml doxycycline prior to treatment with 0.1% DMSO or 100nM AUY922 for 3h

2014-04-15 | E-GEOD-56492 | biostudies-arrayexpress

Identification of targets regulated by HSF1 in response to HSP90 inhibitors

Project description:A375 cells with inducible knockdown HSF1 with and without HSP90 inhibitor treatment A375 cells were seeded in 6-well plates for 3d with 100ng/ml doxycycline prior to treatment with 0.1% DMSO or 100nM HSP990 for 3h

2013-03-06 | E-GEOD-44867 | biostudies-arrayexpress

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