The merging of knowledge from genomics, cellular signal transduction and molecular evolution is producing new paradigms of cancer analysis. Protein kinases have long been understood to initiate and promote malignant cell growth and targeting kinases to fight cancer has been a major strategy within the pharmaceutical industry for over two decades. Despite the initial success of kinase inhibitors (KIs), the ability of cancer to evolve resistance and reprogram oncogenic signaling networks has reduced the efficacy of kinase targeting. The molecular chaperone HSP90 physically supports global kinase function while also acting as an evolutionary capacitor. The Cancer Genome Atlas (TCGA) has compiled a trove of data indicating that a large percentage of tumors overexpress or possess mutant kinases that depend on the HSP90 molecular chaperone complex. Moreover, the overexpression or mutation of parallel activators of kinase activity (PAKA) increases the number of components that promote malignancy and indirectly associate with HSP90. Therefore, targeting HSP90 is predicted to complement kinase inhibitors by inhibiting oncogenic reprogramming and cancer evolution. Based on this hypothesis, consideration should be given by both the research and clinical communities towards combining kinase inhibitors and HSP90 inhibitors (H90Ins) in combating cancer. The purpose of this perspective is to reflect on the current understanding of HSP90 and kinase biology as well as promote the exploration of potential synergistic molecular therapy combinations through the utilization of The Cancer Genome Atlas.
Metastatic pheochromocytoma represents one of the major clinical challenges in the field of neuroendocrine oncology. Recent molecular characterization of pheochromocytoma suggests new treatment options with targeted therapies. In this study we investigated the 90 kDa heat shock protein (Hsp90) as a potential therapeutic target for advanced pheochromocytoma. Both the first generation, natural product Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin), and the second-generation synthetic Hsp90 inhibitor STA-9090 (ganetespib) demonstrated potent inhibition of proliferation and migration of pheochromocytoma cell lines and induced degradation of key Hsp90 clients. Furthermore, ganetespib induced dose-dependent cytotoxicity in primary pheochromocytoma cells. Using metastatic models of pheochromocytoma, we demonstrate the efficacy of 17-AAG and ganetespib in reducing metastatic burden and increasing survival. Levels of Hsp70 in plasma from the xenograft studies served as a proximal biomarker of drug treatment. Our study suggests that targeting Hsp90 may benefit patients with advanced pheochromocytoma.
Background: Englerin A (EA) is a natural product which has shown selective toxicity toward kidney tumor cells in the NCI60 panel. However, EA's targets and mechanism of action remain unknown. Methods: Cytotoxicity of EA toward a panel of kidney cancer cell lines was assessed in vitro by MTT and cell counting, and in vivo using a human clear cell kidney cancer xenograft mouse model. The protein kinase C family was predicted as a likely molecular target of EA using QSAR methodology. This was confirmed by PKC kinase activity assays. EA's mechanism of action was investigated using western-blot analysis, meso-scale discovery technology, and immunohistochemistry. Results: EA was cytotoxic in vitro and in vivo via induction of apoptosis. Comparison of EA's structure with other well-known compounds predicted the PKC family to be a potential drug target. Direct treatment of cell lysates with EA increased pan-PKC kinase activity, suggesting that EA directly activated at least one of the PKC isoforms. Further investigation showed that EA-dependant PKC activation inhibited the insulin pathway through inhibitory phosphorylation of Insulin Receptor Soluble 1 (IRS1) protein, and decreased phosphorylation status of Akt and GSK3beta. These data were reproduced in vivo, as phosphorylation of GSK3beta was reduced in RCC tumor treated with EA compared to tumor treated with vehicle. Conclusion: The insulin/PI3K/Akt pathway has been previously shown by us and others to be critical for the survival of renal cell carcinoma. By activating PKCs, EA indirectly induces an “insulin resistant” phenotype which appears to be selectively lethal for RCC tumor cells. Thus, EA represents a novel potential therapeutic lead for renal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 959. doi:10.1158/1538-7445.AM2011-959
Tonantzitlolone is a diterpene ester first extracted in 1990 from the native Mexican plant Stillingia sanguinolutea (Euphorbiaceae), which displays anti-tumor activity. Although its structure and total synthesis have been elucidated, its cellular target(s) and potential mechanism of action remain unknown. We identified Tonantzitlolone as a dual PKCα and PKCθ activator in vitro. However in clear cell renal cell carcinoma (CCRCC), its activity was mostly PKCθ-dependent. Through activation of PKCθ, Tonantzitlolone induced an insulin-resistant phenotype by inhibiting IRS1 and the PI3K/Akt pathway. Simultaneously, Tonantzitlolone activated the transcription factor heat shock factor 1 (HSF1), driving glucose dependency. Thus, similar to the selective PKCθ activator Englerin A, Tonantzitlolone induces a metabolic catastrophe in CCRCC, starving the cells of glucose while increasing their glycolytic dependency, ultimately leading to cell death. Citation Format: Carole Sourbier, Brad Scroggins, Philip Z. Mannes, John A. Beutler, W. Marston Linehan, Len Neckers. Deciphering the targets and mechanism of action of the natural product Tonantzitlolone in clear cell renal cell carcinomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3202. doi:10.1158/1538-7445.AM2014-3202
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