at-13387 and Lung-Neoplasms

Heat shock protein 90 (Hsp90) protects cellular proteins from degradation by the ubiquitin-proteasome system in conditions of stress. Many cancers have increased expression of Hsp90 to ensure their malignant phenotype of increased proliferation, decreased apoptosis, and metastatic potential by conservation of proteins like epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2, anaplastic lymphoma kinase (ALK), v-Raf murine sarcoma viral oncogene homologue B1, AKT, B-cell lymphoma 2, and cell cycle proteins. This review discusses recent developments in the strategy of Hsp90 inhibition as a targeted therapy in non-small-cell lung cancer (NSCLC).. Hsp90 inhibitors result in growth inhibition and tumor regression in NSCLC cell lines and tumor xenograft models, both as monotherapy and in combination with other drugs. Hsp90 inhibition has particular efficacy in molecular subtypes of NSCLC, such as EGFR-mutated and ALK-rearranged NSCLC. IPI-504 and ganetespib have activity in NSCLC both as monotherapy and in combination with docetaxel.. Preclinical studies and early clinical trials have confirmed the efficacy of Hsp90 inhibition as a targeted therapy in NSCLC. Ongoing trials will further define the utility of Hsp90 inhibitors in NSCLC.

Topics: Benzamides; Benzoquinones; Carcinoma, Non-Small-Cell Lung; HSP90 Heat-Shock Proteins; Humans; Isoindoles; Isoxazoles; Lactams, Macrocyclic; Lung Neoplasms; Molecular Targeted Therapy; Resorcinols; Treatment Outcome; Triazoles

Onalespib is a novel heat shock protein 90 inhibitor (HSP90i). Previous preclinical and clinical studies with HSP90i have demonstrated activity in EGFR-mutant non-small cell lung cancer (NSCLC). This study sought to determine the safety and tolerability of onalespib plus erlotinib in EGFR-mutant NSCLC and to evaluate the preliminary efficacy of the combination in epidermal growth factor receptor exon 20 insertion (EGFRex20ins) NSCLC.. Standard 3+3 dose escalation was followed by a phase II expansion in EGFRex20ins. The phase II component targeted a response rate of 25% versus a background rate of 5%. Prospective next-generation sequencing (NGS) of 70 cancer-related genes, including EGFR, via plasma circulating tumor DNA (ctDNA) was performed. Toxicity was graded by Common Terminology Criteria for Adverse Events (CTCAE), version 4, and response was determined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1.. Eleven patients were treated (nine dose escalation, two dose expansion). Two dose-limiting toxicities (DLTs) occurred in dose level (DL) 0 and zero in DL -1 (minus). In 10 EGFRex20ins patients, no responses were observed, median progression-free survival was 5.4 months (95% confidence interval, 0.9-5.7), and the disease control rate (DCR) was 40% (median, 3.5 months). EGFRex20ins was detected in nine of 10 ctDNA samples at baseline; on-treatment ctDNA clearance was not observed. Grade 3 diarrhea was the predominant toxicity in 45% of patients. The recommended phase II dose is DL -1 (minus): erlotinib 150 mg orally every morning and onalespib 120 mg/m. Overlapping toxicities of erlotinib and onalespib, mainly diarrhea, limited the tolerability of this combination, and limited clinical activity was observed, so the trial was closed early. Plasma EGFRex20ins ctDNA was detected in the majority of patients; failure to clear ctDNA was consistent with lack of tumor response (NCT02535338).

Topics: Aged; Benzamides; California; ErbB Receptors; Erlotinib Hydrochloride; Female; Humans; Isoindoles; Lactates; Lung Neoplasms; Male; Middle Aged; Mutation; Prospective Studies

Recent preclinical studies suggest combining the HSP90 inhibitor AT13387 (Onalespib) with radiation (IR) against colon cancer and head and neck squamous cell carcinoma (HNSCC). These studies emphasized that AT13387 downregulates HSP90 client proteins involved in oncogenic signaling and DNA repair mechanisms as major drivers of enhanced radiosensitivity. Given the large array of client proteins HSP90 directs, we hypothesized that other key proteins or signaling pathways may be inhibited by AT13387 and contribute to enhanced radiosensitivity. Metabolomic analysis of HSP90 inhibition by AT13387 was conducted to identify metabolic biomarkers of radiosensitization and whether modulations of key proteins were involved in IR-induced tumor vasculogenesis, a process involved in tumor recurrence.. HNSCC and non-small cell lung cancer cell lines were used to evaluate the AT13387 radiosensitization effect in vitro and in vivo. Flow cytometry, immunofluorescence, and immunoblot analysis were used to evaluate cell cycle changes and HSP90 client protein's role in DNA damage repair. Metabolic analysis was performed using liquid chromatography-Mass spectrometry. Immunohistochemical examination of resected tumors post-AT13387 and IR treatment were conducted to identify biomarkers of IR-induced tumor vasculogenesis.. In agreement with recent studies, AT13387 treatment combined with IR resulted in a G2/M cell cycle arrest and inhibited DNA repair. Metabolomic profiling indicated a decrease in key metabolites in glycolysis and tricarboxylic acid cycle by AT13387, a reduction in Adenosine 5'-triphosphate levels, and rate-limiting metabolites in nucleotide metabolism, namely phosphoribosyl diphosphate and aspartate. HNSCC xenografts treated with the combination exhibited increased tumor regrowth delay, decreased tumor infiltration of CD45 and CD11b+ bone marrow-derived cells, and inhibition of HIF-1 and SDF-1 expression, thereby inhibiting IR-induced vasculogenesis.. AT13387 treatment resulted in pharmacologic inhibition of cancer cell metabolism that was linked to DNA damage repair. AT13387 combined with IR inhibited IR-induced vasculogenesis, a process involved in tumor recurrence postradiotherapy. Combining AT13387 with IR warrants consideration of clinical trial assessment.

Topics: Animals; Aspartic Acid; Benzamides; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Line, Tumor; Colonic Neoplasms; DNA Damage; DNA Repair; Down-Regulation; G2 Phase Cell Cycle Checkpoints; Head and Neck Neoplasms; HSP90 Heat-Shock Proteins; Humans; Isoindoles; Lung Neoplasms; M Phase Cell Cycle Checkpoints; Metabolomics; Mice; Mice, Nude; Neoplasm Recurrence, Local; Neovascularization, Pathologic; Nucleotides; Radiation Tolerance; Squamous Cell Carcinoma of Head and Neck; Xenograft Model Antitumor Assays

Tyrosine 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.. The HSP90 inhibitor, onalespib, was combined with either crizotinib or erlotinib in ALK- or EGFR-activated xenograft models respectively (H2228, HCC827).. In 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.. Together, these preclinical data suggest that frontline combination with an HSP90 inhibitor may be a method for delaying the emergence of resistance to targeted therapies.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Crizotinib; Drug Resistance, Neoplasm; Erlotinib Hydrochloride; HSP90 Heat-Shock Proteins; Humans; Isoindoles; Lung Neoplasms; Male; Mice, Inbred BALB C; Mice, SCID; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Xenograft Model Antitumor Assays

A ubiquitously expressed chaperone, heat shock protein 90 (HSP90) is of considerable interest as an oncology target because tumor cells and oncogenic proteins are acutely dependent on its activity. AT13387 (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindol-2-yl] methanone, l-lactic acid salt) a novel, high-affinity HSP90 inhibitor, which is currently being clinically tested, has shown activity against a wide array of tumor cell lines, including lung cancer cell lines. This inhibitor has induced the degradation of specific HSP90 client proteins for up to 7 days in tumor cell lines in vitro. The primary driver of cell growth (mutant epidermal growth factor receptors) was particularly sensitive to HSP90 inhibition. The long duration of client protein knockdown and suppression of phospho-signaling seen in vitro after treatment with AT13387 was also apparent in vivo, with client proteins and phospho-signaling suppressed for up to 72 h in xenograft tumors after treatment with a single dose of AT13387. Pharmacokinetic analyses indicated that while AT13387 was rapidly cleared from blood, its retention in tumor xenografts was markedly extended, and it was efficacious in a range of xenograft models. AT13387's long duration of action enabled, in particular, its efficacious once weekly administration in human lung carcinoma xenografts. The use of longer-acting HSP90 inhibitors, such as AT13387, on less frequent dosing regimens has the potential to maintain antitumor efficacy as well as minimize systemic exposure and unwanted effects on normal tissues.

Topics: Animals; Antineoplastic Agents; Benzamides; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; HSP90 Heat-Shock Proteins; Humans; Isoindoles; Lung Neoplasms; Male; Mice; Mice, Nude; Xenograft Model Antitumor Assays

The epidermal growth factor receptor (EGFR) has been targeted for inhibition using tyrosine kinase inhibitors and monoclonal antibodies, with improvement in outcome in subsets of patients with head and neck, lung, and colorectal carcinomas. We have previously found that EGFR stability plays a key role in cell survival after chemotherapy and radiotherapy. Heat shock protein 90 (HSP90) is known to stabilize mutant EGFR and ErbB2, but its role in cancers with wild-type (WT) WT-EGFR is unclear. In this report, we demonstrate that fully mature, membrane-bound WT-EGFR interacts with HSP90 independent of ErbB2. Further, the HSP90 inhibitors geldanamycin (GA) and AT13387 cause a decrease in WT-EGFR in cultured head and neck cancer cells. This decrease results from a significantly reduced half-life of WT-EGFR. WT-EGFR was also lost in head and neck xenograft specimens after treatment with AT13387 under conditions that inhibited tumor growth and prolonged survival of the mice. Our findings demonstrate that WT-EGFR is a client protein of HSP90 and that their interaction is critical for maintaining both the stability of the receptor as well as the growth of EGFR-dependent cancers. Furthermore, these findings support the search for specific agents that disrupt HSP90's ability to act as an EGFR chaperone.

Topics: Animals; Antibiotics, Antineoplastic; Benzamides; Benzoquinones; Cell Line, Tumor; Cell Proliferation; Cell Survival; CHO Cells; Cricetinae; ErbB Receptors; Head and Neck Neoplasms; HSP90 Heat-Shock Proteins; Humans; Isoindoles; Lactams, Macrocyclic; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, SCID; Receptor, ErbB-2; Transplantation, Heterologous