http://lindquistlab.wi.mit.edu/wp-content/uploads/2013/06/Taipale_2012.pdf

Quantitative Analysis of Hsp90-Client Interactions Reveals Principles of Substrate Recognition

Lung cancer with epidermal growth factor receptor (EGFR)-activating mutations responds favorably to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. However, 25% to 30% of patients with EGFR-activating mutations show intrinsic resistance, and the responders invariably acquire resistance to gefitinib. Here, we showed that hepatocyte growth factor (HGF), a ligand of MET oncoprotein, induces gefitinib resistance of lung adenocarcinoma cells with EGFR-activating mutations by restoring the phosphatidylinositol 3-kinase/Akt signaling pathway via phosphorylation of MET, but not EGFR or ErbB3. Strong immunoreactivity for HGF in cancer cells was detected in lung adenocarcinoma patients harboring EGFR-activating mutations, but no T790M mutation or MET amplification, who showed intrinsic or acquired resistance to gefitinib. The findings indicate that HGF-mediated MET activation is a novel mechanism of gefitinib resistance in lung adenocarcinoma with EGFR-activating mutations. Therefore, inhibition of HGF-MET signaling may be a considerable strategy for more successful treatment with gefitinib.

Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations

Heat shock proteins (HSPs) are a large family of chaperones that are involved in protein folding and maturation of a variety of “client” proteins protecting them from degradation, oxidative stress, hypoxia, and thermal stress. Hence, they are significant regulators of cellular proliferation, differentiation and strongly implicated in the molecular orchestration of cancer development and progression as many of their clients are well established oncoproteins in multiple tumor types. Interestingly, tumor cells are more HSP chaperonage-dependent than normal cells for proliferation and survival because the oncoproteins in cancer cells are often misfolded and require augmented chaperonage activity for correction. This led to the development of several inhibitors of HSP90 and other HSPs that have shown promise both preclinically and clinically in the treatment of cancer. In this article, we comprehensively review the roles of some of the important HSPs in cancer, and how targeting them could be efficacious, especially when traditional cancer therapies fail.

Targeting Heat Shock Proteins in Cancer: A Promising Therapeutic Approach

A Quantitative Chaperone Interaction Network Reveals the Architecture of Cellular Protein Homeostasis Pathways

Novel hotspot mutant p53 gain-of-function mouse model shows that tumours depend on its sustained expression, and genetic and pharmacological approaches reveal mutant p53 as an actionable cancer drug target The tumour suppressor TP53 is one of the most frequently mutated genes in human cancer Although some genetic alterations cause its complete loss, many are gain-of-function mutations in which mutant p53 protein gains new properties that promote tumorigenesis Ute Moll and colleagues now demonstrate in a mouse model that expression of such a p53 mutant is needed not only for tumour initiation but also for tumour maintenance They further show that they can target mutant p53 indirectly by inhibiting a chaperone called Hsp90 which is needed to keep mutant p53 protein stable In a mouse model of lymphoma, this approach led to degradation of mutant p53 and reduced tumour growth Missense mutations in p53 generate aberrant proteins with abrogated tumour suppressor functions that can also acquire oncogenic gain-of-function activities that promote malignant progression, invasion, metastasis and chemoresistance1,2,3,4,5 Mutant p53 (mutp53) proteins undergo massive constitutive stabilization specifically in tumours, which is the key requisite for the acquisition of gain-of-functions activities6,7,8 Although currently 11 million patients worldwide live with tumours expressing highly stabilized mutp53, it is unknown whether mutp53 is a therapeutic target in vivo Here we use a novel mutp53 mouse model expressing an inactivatable R248Q hotspot mutation (floxQ) to show that tumours depend on sustained mutp53 expression Upon tamoxifen-induced mutp53 ablation, allotransplanted and autochthonous tumours curb their growth, thus extending animal survival by 37%, and advanced tumours undergo apoptosis and tumour regression or stagnation The HSP90/HDAC6 chaperone machinery, which is significantly upregulated in cancer compared with normal tissues, is a major determinant of mutp53 stabilization9,10,11,12 We show that long-term HSP90 inhibition significantly extends the survival of mutp53 Q/− (R248Q allele2) and H/H (R172H allele3) mice by 59% and 48%, respectively, but not their corresponding p53−/− littermates This mutp53-dependent drug effect occurs in H/H mice treated with 17DMAG+SAHA and in H/H and Q/− mice treated with the potent Hsp90 inhibitor ganetespib Notably, drug activity correlates with induction of mutp53 degradation, tumour apoptosis and prevention of T-cell lymphomagenesis These proof-of-principle data identify mutp53 as an actionable cancer-specific drug target

Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment

Targeted inhibition of the molecular chaperone Hsp90 results in the simultaneous blockade of multiple oncogenic signaling pathways and has, thus, emerged as an attractive strategy for the development of novel cancer therapeutics. Ganetespib (formerly known as STA-9090) is a unique resorcinolic triazolone inhibitor of Hsp90 that is currently in clinical trials for a number of human cancers. In the present study, we showed that ganetespib exhibits potent in vitro cytotoxicity in a range of solid and hematologic tumor cell lines, including those that express mutated kinases that confer resistance to small-molecule tyrosine kinase inhibitors. Ganetespib treatment rapidly induced the degradation of known Hsp90 client proteins, displayed superior potency to the ansamycin inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), and exhibited sustained activity even with short exposure times. In vivo, ganetespib showed potent antitumor efficacy in solid and hematologic xenograft models of oncogene addiction, as evidenced by significant growth inhibition and/or regressions. Notably, evaluation of the microregional activity of ganetespib in tumor xenografts showed that ganetespib was efficiently distributed throughout tumor tissue, including hypoxic regions >150 μm from the microvasculature, to inhibit proliferation and induce apoptosis. Importantly, ganetespib showed no evidence of cardiac or liver toxicity. Taken together, this preclinical activity profile indicates that ganetespib may have broad application for a variety of human malignancies, and with select mechanistic and safety advantages over other first- and second-generation Hsp90 inhibitors.

https://mct.aacrjournals.org/content/molcanther/11/2/475.full.pdf

Ganetespib, a Unique Triazolone-Containing Hsp90 Inhibitor, Exhibits Potent Antitumor Activity and a Superior Safety Profile for Cancer Therapy

Systemic chemotherapy using two-drug platinum-based regimens for the treatment of advanced stage non-small cell lung cancer (NSCLC) has largely reached a plateau of effectiveness. Accordingly, efforts to improve survival and quality of life outcomes have more recently focused on the use of molecularly targeted agents, either alone or in combination with standard of care therapies such as taxanes. The molecular chaperone heat shock protein 90 (Hsp90) represents an attractive candidate for therapeutic intervention, as its inhibition results in the simultaneous blockade of multiple oncogenic signaling cascades. Ganetespib is a non-ansamycin inhibitor of Hsp90 currently under clinical evaluation in a number of human malignancies, including NSCLC. Here we show that ganetespib potentiates the cytotoxic activity of the taxanes paclitaxel and docetaxel in NSCLC models. The combination of ganetespib with paclitaxel, docetaxel or another microtubule-targeted agent vincristine resulted in synergistic antiproliferative effects in the H1975 cell line in vitro. These benefits translated to improved efficacy in H1975 xenografts in vivo, with significantly enhanced tumor growth inhibition observed in combination with paclitaxel and tumor regressions seen with docetaxel. Notably, concurrent exposure to ganetespib and docetaxel improved antitumor activity in 5 of 6 NSCLC xenograft models examined. Our data suggest that the improved therapeutic indices are likely to be mechanistically multifactorial, including loss of pro-survival signaling and direct cell cycle effects resulting from Hsp90 modulation by ganetespib. Taken together, these findings provide preclinical evidence for the use of this combination to treat patients with advanced NSCLC.

/pdf/synergistic-activity-of-the-hsp90-inhibitor-ganetespib-with-2wpdptghfc.pdf

Synergistic activity of the Hsp90 inhibitor ganetespib with taxanes in non-small cell lung cancer models

Targeted inhibition of the molecular chaperone heat shock protein 90 (Hsp90) results in the simultaneous blockade of multiple oncogenic signaling pathways and has thus emerged as an attractive strategy for the development of novel cancer therapeutics. Ganetespib (STA-9090) is a unique resorcinolic inhibitor of Hsp90 currently in clinical trials for a number of human cancers. Here we describe the key interaction of ganetespib with a number of amino acid residues in the ATP binding pocket of Hsp90 which results in high affinity binding. Ganetespib exhibits potent in vitro cytotoxicity in a range of solid and hematological tumor cell lines. By using a novel isotope-labeling scheme and LC-MS/MS detection technique, we have determined that Hsp90 occupancy by ganetespib in cancer cells is relatively fast under saturating conditions, reaching equilibrium within 5 minutes of ganetespib exposure. In vivo, ganetespib demonstrated strong single-agent activity in solid and hematological xenograft models, as evidenced by significant tumor growth inhibition and/or regression. Of note, evaluation of the microregional activity of ganetespib in tumor xenografts showed that ganetespib efficiently distributed throughout tumor tissue, including hypoxic regions >150 m from the microvasculature, to inhibit proliferation and induce apoptosis. Most importantly, ganetespib showed no evidence of cardiac or liver toxicity and exhibited minimal potential risk for CNS or ocular toxicities. Taken together, this preclinical activity profile suggests that ganetespib may have broad application for a variety of human malignancies and mechanistic and safety advantages over other first- and second-generation Hsp90 inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B105.

Abstract B105: Ganetespib, a unique resorcinolic Hsp90 inhibitor, exhibits potent antitumor activity and a superior safety profile in preclinical models.

Shuxia Ye

Papers

Ganetespib, a Unique Triazolone-Containing Hsp90 Inhibitor, Exhibits Potent Antitumor Activity and a Superior Safety Profile for Cancer Therapy

Synergistic activity of the Hsp90 inhibitor ganetespib with taxanes in non-small cell lung cancer models

Abstract B105: Ganetespib, a unique resorcinolic Hsp90 inhibitor, exhibits potent antitumor activity and a superior safety profile in preclinical models.