Open AccessJournal Article
HSP90 inhibitors in lung cancer: promise still unfulfilled.
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TLDR
This review discusses the development and the preclinical and clinical profiles of some of the HSP90 inhibitors that may help to improve the targeted treatment of NSCLC.Abstract:
Despite recent advances in the treatment of lung cancer, non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths in the United States and worldwide, with a 5-year survival rate of less than 17%. Analysis of the molecular drivers of NSCLC led to the recognition that NSCLC is a collection of distinct, molecularly driven neoplasms. Several subsets of NSCLC with clinical relevance to targeted therapies are defined based on alterations in EGFR, ALK, and other key oncogenic drivers. However, for many oncogenic drivers-such as mutant KRAS-targeted therapies are lacking. Heat shock protein 90 (HSP90) is an adenosine triphosphate (ATP)-dependent molecular chaperone that is critically required for the stability of its clientele, many of which are driver oncoproteins. Therefore, HSP90 inhibitors could prove to be an effective and alternate approach to treat patients with NSCLC that has a specific molecular background or that has acquired resistance to other drugs. Over the last 2 decades, several HSP90 inhibitors have been developed that produced promising preclinical and clinical results. The quest is far from over, however. In this review, we discuss the development and the preclinical and clinical profiles of some of the HSP90 inhibitors that may help to improve the targeted treatment of NSCLC.read more
Citations
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Induced protein degradation: an emerging drug discovery paradigm
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Targeting Heat Shock Proteins in Cancer: A Promising Therapeutic Approach
TL;DR: The roles of some of the important HSPs in cancer are reviewed, and how targeting them could be efficacious, especially when traditional cancer therapies fail are reviewed.
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Targeted Protein Degradation: from Chemical Biology to Drug Discovery.
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Collateral sensitivity networks reveal evolutionary instability and novel treatment strategies in ALK mutated non-small cell lung cancer.
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Heat Shock Proteins Are Essential Components in Transformation and Tumor Progression: Cancer Cell Intrinsic Pathways and Beyond.
Benjamin J. Lang,Martin E. Guerrero-Gimenez,Thomas L. Prince,Andrew Ackerman,Cristina Bonorino,Stuart K. Calderwood +5 more
TL;DR: Findings of a triple role for elevated HSP expression in tumorigenesis strongly support the targeting of HSPs in cancer, especially given the role of such stress proteins in resistance to conventional therapies.
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TL;DR: The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients, and the drug resulted in grade 1 or 2 gastrointestinal side effects.
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Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain
William Pao,Vincent A. Miller,Katerina Politi,Gregory J. Riely,Romel Somwar,Maureen F. Zakowski,Mark G. Kris,Harold E. Varmus +7 more
TL;DR: Biochemical analyses of transfected cells and growth inhibition studies with lung cancer cell lines demonstrate that the T790M mutation confers resistance to EGFR mutants usually sensitive to either gefitinib or erlotinib, which should help guide the search for more effective therapy against a specific subset of lung cancers.
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Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors
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TL;DR: Detailed genetic and histological analysis of 37 patients with drug-resistant non–small cell lung cancers carrying EGFR mutations provides new insights into the shifting sands of drug resistance evolution in lung cancers and suggests that serial biopsies may be essential in the quest to reverse or even prevent the development ofdrug resistance.