title: Heat shock protein antagonists in early stage clinical trials for NSCLC.
abstract: Cancer cells have a higher need of chaperones than normal cells to prevent the toxic effects of intracellular protein misfolding and aggregation. Heat shock proteins (Hsps) belong to these chaperones; they are classified into families according to molecular size. Hsps are upregulated in many cancers and inhibition can inhibit tumor growth by destabilizing proteins necessary for tumor survival. In non-small cell lung cancer (NSCLC), there are three different Hsp antagonist classes that are in (early) clinical trials: Hsp90, Hsp70 and Hsp27 inhibitors. Areas covered: The rationale to use Hsp inhibitors in NSCLC will be summarized and phase I-III trials will be reviewed. Expert opinion: Several Hsp90 inhibitors have been tested in phase I-III trials, until now none was positive in unselected NSCLC; therefore development of AUY922, ganetespib and retaspimycin was halted. Results seem more promising in molecularly selected patients, especially in ALK-rearranged NSCLC. Hsp27 is overexpressed in squamous NSCLC and is a mechanism of chemotherapy resistance. The Hsp27 inhibitor apatorsen is now tested in squamous NSCLC. No phase II/III data are known for Hsp70 inhibitors. Combination of Hsp inhibitors with heat shock transcription factor 1 inhibitors or focal adhesion kinase inhibitors might be of interest for future trials.
authors.affiliation: a Department of Pulmonary Diseases, GROW - School for oncology and developmental biology , Maastricht University Medical Center+ , Maastricht , The Netherlands.
authors.forename: Lizza E L
authors.initials: LEL
authors.lastname: Hendriks
authors.affiliation: a Department of Pulmonary Diseases, GROW - School for oncology and developmental biology , Maastricht University Medical Center+ , Maastricht , The Netherlands.
authors.forename: Anne-Marie C
authors.initials: AC
authors.lastname: Dingemans
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D015195:Drug Design; D055551:HSP27 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D018579:Patient Selection
chemical_list: D000970:Antineoplastic Agents; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D006360:Heat-Shock Proteins
keywords: Early clinical trials; Hsp27 inhibitors; Hsp70 inhibitors; Hsp90 inhibitors; non-small cell lung cancer