sta-9090 and Lung-Neoplasms

Heat shock proteins (Hsps) are part of a complex network of chaperone proteins that are critically involved in the conformational maturation of intracellular proteins and regulate their degradation via the proteasome system Hsps (especially Hsp70 and Hsp90) are upregulated in many cancers and are potentially attractive therapeutic targets. Ganetespib is a potent non-geldanamycin analogue, and avoids the toxicities associated with older analogues due to its small molecular weight, lipophilicity and the absence of the benzoquinone moiety; strong pre-clinical data support its evaluation in lung cancer, especially small cell lung cancer (SCLC). Areas covered: The chemical structure of ganetespib, the biology of Hsp90 in cancer and the pharmacokinetic and pharmacodynamic data related to ganetespib are summarized; data from preclinical studies and multiple Phase I-III clinical trials, with a focus on its evaluation in SCLC are reviewed. Expert opinion: Recent progress made in the treatment of refractory SCLC with immune checkpoint inhibitors and DLL3-directed antibody-drug conjugate have made the development of ganetespib particularly challenging in SCLC. Hsp90 remains a critical therapeutic target. Hsp90 inhibitors with a wider therapeutic index and combinations with drugs targeting iHsp90 co-chaperones such as Cdc37 or Protein Kinase 2 may need to be explored in the future.

Topics: Animals; Antineoplastic Agents; HSP90 Heat-Shock Proteins; Humans; Lung Neoplasms; Molecular Weight; Small Cell Lung Carcinoma; Triazoles; Up-Regulation

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

Topics: Apoptosis; Benzoquinones; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Lung Neoplasms; Mutation; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Triazoles

This trial was designed to evaluate the activity and safety of ganetespib in combination with docetaxel in advanced non-small cell lung cancer (NSCLC) and to identify patient populations most likely to benefit from the combination.. Patients with one prior systemic therapy for advanced disease were eligible. Docetaxel (75 mg/m(2) on day 1) was administered alone or with ganetespib (150 mg/m(2) on days 1 and 15) every 3 weeks. The primary end points were progression-free survival (PFS) in two subgroups of the adenocarcinoma population: patients with elevated lactate dehydrogenase (eLDH) and mutated KRAS (mKRAS).. Of 385 patients enrolled, 381 were treated. Early in the trial, increased hemoptysis and lack of efficacy were observed in nonadenocarcinoma patients (n = 71); therefore, only patients with adenocarcinoma histology were subsequently enrolled. Neutropenia was the most common grade ≥3 adverse event: 41% in the combination arm versus 42% in docetaxel alone. There was no improvement in PFS for the combination arm in the eLDH (N = 114, adjusted hazard ratio (HR) = 0.77, P = 0.1134) or mKRAS (N = 89, adjusted HR = 1.11, P = 0.3384) subgroups. In the intent-to-treat adenocarcinoma population, there was a trend in favor of the combination, with PFS (N = 253, adjusted HR = 0.82, P = 0.0784) and overall survival (OS) (adjusted HR = 0.84, P = 0.1139). Exploratory analyses showed significant benefit of the ganetespib combination in the prespecified subgroup of adenocarcinoma patients diagnosed with advanced disease >6 months before study entry (N = 177): PFS (adjusted HR = 0.74, P = 0.0417); OS (adjusted HR = 0.69, P = 0.0191).. Advanced lung adenocarcinoma patients treated with ganetespib in combination with docetaxel had an acceptable safety profile. While the study's primary end points were not met, significant prolongation of PFS and OS was observed in patients >6 months from diagnosis of advanced disease, a subgroup chosen as the target population for the phase III study.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Docetaxel; Female; HSP90 Heat-Shock Proteins; Humans; L-Lactate Dehydrogenase; Lung Neoplasms; Male; Middle Aged; Proportional Hazards Models; Proto-Oncogene Proteins p21(ras); Taxoids; Treatment Outcome; Triazoles

EML4-ALK gene rearrangements define a unique subset of patients with non-small cell lung carcinoma (NSCLC), and the clinical success of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib in this population has become a paradigm for molecularly targeted therapy. Here, we show that the Hsp90 inhibitor ganetespib induced loss of EML4-ALK expression and depletion of multiple oncogenic signaling proteins in ALK-driven NSCLC cells, leading to greater in vitro potency, superior antitumor efficacy, and prolonged animal survival compared with results obtained with crizotinib. In addition, combinatorial benefit was seen when ganetespib was used with other targeted ALK agents both in vitro and in vivo. Importantly, ganetespib overcame multiple forms of crizotinib resistance, including secondary ALK mutations, consistent with activity seen in a patient with crizotinib-resistant NSCLC. Cancer cells driven by ALK amplification and oncogenic rearrangements of ROS1 and RET kinase genes were also sensitive to ganetespib exposure. Taken together, these results highlight the therapeutic potential of ganetespib for ALK-driven NSCLC.. In addition to direct kinase inhibition, pharmacologic blockade of the molecular chaperone Hsp90 is emerging as a promising approach for treating tumors driven by oncogenic rearrangements of ALK. The bioactivity profi le of ganetespib presented here underscores a new therapeutic opportunity to target ALK and overcome multiple mechanisms of resistance in patients with ALK-positive NSCLC.

Topics: Adult; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Crizotinib; Drug Resistance, Neoplasm; Female; HSP90 Heat-Shock Proteins; Humans; Lung Neoplasms; Male; Mice; Mice, Nude; Mice, SCID; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Triazoles; Tumor Burden; Xenograft Model Antitumor Assays; Young Adult

Ganetespib is a novel inhibitor of the heat shock protein 90 (Hsp90), a chaperone protein critical to tumor growth and proliferation. In this phase II study, we evaluated the activity and tolerability of ganetespib in previously treated patients with non-small cell lung cancer (NSCLC).. Patients were enrolled into cohort A (mutant EGFR), B (mutant KRAS), or C (no EGFR or KRAS mutations). Patients were treated with 200 mg/m(2) ganetespib by intravenous infusion once weekly for 3 weeks followed by 1 week of rest, until disease progression. The primary endpoint was progression-free survival (PFS) at 16 weeks. Secondary endpoints included objective response (ORR), duration of treatment, tolerability, median PFS, overall survival (OS), and correlative studies.. Ninety-nine patients with a median of 2 prior systemic therapies were enrolled; 98 were assigned to cohort A (n = 15), B (n = 17), or C (n = 66), with PFS rates at 16 weeks of 13.3%, 5.9%, and 19.7%, respectively. Four patients (4%) achieved partial response (PR); all had disease that harbored anaplastic lymphoma kinase (ALK) gene rearrangement, retrospectively detected by FISH (n = 1) or PCR-based assays (n = 3), in crizotinib-naïve patients enrolled to cohort C. Eight patients (8.1%) experienced treatment-related serious adverse events (AE); 2 of these (cardiac arrest and renal failure) resulted in death. The most common AEs were diarrhea, fatigue, nausea, and anorexia.. Ganetespib monotherapy showed a manageable side effect profile as well as clinical activity in heavily pretreated patients with advanced NSCLCs, particularly in patients with tumors harboring ALK gene rearrangement.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Female; Gene Rearrangement; Genotype; HSP90 Heat-Shock Proteins; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Neoplasm Staging; Receptor Protein-Tyrosine Kinases; Treatment Outcome; Triazoles

Topics: Afatinib; Animals; Antineoplastic Agents; Benzamides; Cell Cycle Checkpoints; Cell Line; Cell Membrane Permeability; Cell Movement; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Drug Stability; ErbB Receptors; Half-Life; HSP90 Heat-Shock Proteins; Humans; Lung Neoplasms; Rats; Resorcinols; Transplantation, Heterologous

Topics: A549 Cells; Animals; Antineoplastic Agents; Antioxidants; Carcinoma, Non-Small-Cell Lung; Cerium; CHO Cells; Combined Modality Therapy; Cricetinae; Cricetulus; Glycolipids; Histone Deacetylase Inhibitors; HSP90 Heat-Shock Proteins; Humans; Lung Neoplasms; Triazoles

A major cause of failure of therapy in patients with non-small cell lung cancer (NSCLC) is development of acquired drug resistance leading to tumor recurrence and disease progression. In addition to the development of new generations of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), different molecular targets may provide opportunities to improve the therapeutic outcomes. In this study, we utilized the core structure 5-fluorouracil (5-FU) or tegafur, a 5-FU prodrug combined through different linkers with resorcinol to generate a series of fluoropyrimidin-2,4-dihydroxy-5-isopropylbenzamides which inhibit potent Heat Shock Protein 90 (HSP90). These compounds were found to show significant antiproliferative activity in colorectal cancer (CRC) HCT116 and NSCLC A549, H460, and H1975 (EGFR L858R/T790 M double mutation) cells. Compound 12c, developed by molecular docking analysis and enzymatic assays exhibits promising inhibitory activity of HSP90. This compound, 12c shows the most potent HSP90 inhibitory activity with an IC

Topics: Antineoplastic Agents; Apoptosis; Benzamides; Carcinoma, Non-Small-Cell Lung; Caspases; Cell Line, Tumor; Colorectal Neoplasms; Cytoprotection; Enzyme Activation; ErbB Receptors; Humans; Inhibitory Concentration 50; Lung Neoplasms; Mutation; Proteolysis; Proto-Oncogene Proteins c-akt

Topics: A549 Cells; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; CHO Cells; Cricetulus; Humans; Lung Neoplasms; Magnetic Fields; Magnetite Nanoparticles; Nanomedicine; Organoplatinum Compounds; Proto-Oncogene Proteins p21(ras); Triazoles

The 90-kDa heat-shock protein (HSP90) is a chaperone protein expressed at high levels in cancer cells and is involved in the folding or stabilization of several client proteins, including epidermal growth factor receptor (EGFR). Ganetespib is a second-generation HSP90 inhibitor with a potent antitumor effect against various cancer types.. This study examined the antitumor effect of ganetespib in EGFR-mutant non-small cell lung cancer (NSCLC) cells and experimentally established EGFR-tyrosine kinase inhibitor (TKI)-resistant cells harboring various resistance mechanisms, including EGFR T790M mutation, met proto-oncogene amplification, and epithelial-mesenchymal transition.. Ganetespib showed a potent antitumor effect at low concentrations, suppressing EGFR-related downstream pathway molecules and inducing cleavage of poly ADP-ribose polymerase in all examined EGFR-TKI-resistant cell lines in vitro. Ganetespib also inhibited in vivo tumor growth in resistant cells harboring EGFR T790M.. Ganetespib might be a promising therapeutic option for the treatment of patients with EGFR-TKI-resistant NSCLC.

Topics: Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; ErbB Receptors; Female; HSP90 Heat-Shock Proteins; Humans; Lung Neoplasms; Mice, Inbred BALB C; Mice, Nude; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Mas; Signal Transduction; Triazoles; Tumor Burden; Xenograft Model Antitumor Assays

Adaptive resistance to therapy is a hallmark of cancer progression. To date, it is not entirely clear how microenvironmental stimuli would mediate emergence of therapy-resistant cell subpopulations, although a rearrangement of the cancer cell secretome following therapy-induced stress can be pivotal for such a process. Here, by using the highly chemoresistant malignant pleural mesothelioma (MPM) as an experimental model, we unveiled a key contribution of the chaperone HSP90 at assisting a chemotherapy-instigated Senescence-Associated-Secretory-Phenotype (SASP). Thus, administration of a clinical trial grade, HSP90, inhibitor blunted the release of several cytokines by the chemotherapy-treated MPM cells, including interleukin (IL)-8. Reduction of IL-8 levels hampered the FAK-AKT signaling and inhibited 3D growth and migration. This correlated with downregulation of key EMT and chemoresistance genes and affected the survival of chemoresistant ALDH

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cellular Senescence; Cisplatin; Drug Resistance, Neoplasm; HSP90 Heat-Shock Proteins; Humans; Lung Neoplasms; Male; Mesothelioma; Mesothelioma, Malignant; Mice; Mice, Inbred NOD; Mice, SCID; Pemetrexed; Secretory Pathway; Triazoles

Macroautophagy/autophagy has emerged as a resistance mechanism to anticancer drug treatments that induce metabolic stress. Certain tumors, including a subset of KRAS-mutant NSCLCs have been shown to be addicted to autophagy, and potentially vulnerable to autophagy inhibition. Currently, autophagy inhibition is being tested in the clinic as a therapeutic component for tumors that utilize this degradation process as a drug resistance mechanism. The current study provides evidence that HSP90 (heat shock protein 90) inhibition diminishes the expression of ATG7, thereby impeding the cellular capability of mounting an effective autophagic response in NSCLC cells. Additionally, an elevation in the expression level of CASP9 (caspase 9) prodomain in KRAS-mutant NSCLC cells surviving HSP90 inhibition appears to serve as a cell survival mechanism. Initial characterization of this survival mechanism suggests that the altered expression of CASP9 is mainly ATG7 independent; it does not involve the apoptotic activity of CASP9; and it localizes to a late endosomal and pre-lysosomal phase of the degradation cascade. HSP90 inhibitors are identified here as a pharmacological approach for targeting autophagy via destabilization of ATG7, while an induced expression of CASP9, but not its apoptotic activity, is identified as a resistance mechanism to the cellular stress brought about by HSP90 inhibition.

Topics: Autophagy; Autophagy-Related Protein 7; Carcinoma, Non-Small-Cell Lung; Caspase 9; Cell Line, Tumor; Cytoprotection; Down-Regulation; Drug Resistance, Neoplasm; Enzyme Stability; HSP90 Heat-Shock Proteins; Humans; Lung Neoplasms; Mutation; Protein Domains; Triazoles; Up-Regulation

K-RAS driven non-small-cell lung cancer (NSCLC) represents a major cause of death among smokers. Recently, nanotechnology has introduced novel avenues for the diagnosis and personalized treatment options for cancer. Herein, we report a novel, multifunctional nanoceria platform loaded with a unique combination of two therapeutic drugs, doxorubicin (Doxo) and Hsp90 inhibitor ganetespib (GT), for the diagnosis and effective treatment of NSCLC. We hypothesize that the use of ganetespib synergizes and accelerates the therapeutic efficacy of Doxo via ROS production, while minimizing the potential cardiotoxicity of doxorubicin drug. Polyacrylic acid (PAA)-coated cerium oxide nanoparticles (PNC) were fabricated for the targeted combination therapy of lung cancers. Using "click" chemistry, the surface carboxylic acid groups of nanoceria were decorated with folic acid to target folate-receptor-overexpressing NSCLC. As a result of combination therapy, results showed more than 80% of NSCLC death within 48 h of incubation. These synergistic therapeutic effects were assessed via enhanced ROS, cytotoxicity, apoptosis, and migration assays. Overall, these results indicated that the targeted codelivery of Doxo and GT using nanoceria may offer an alternative combination therapy option for the treatment of undruggable NSCLC.

Topics: A549 Cells; Acrylic Resins; Animals; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cerium; Combined Modality Therapy; Doxorubicin; Drug Carriers; Folic Acid; HSP90 Heat-Shock Proteins; Humans; Lung Neoplasms; Nanoparticles; Rats; Reactive Oxygen Species; Triazoles

HSP90 inhibition is well known to sensitize cancer cells to radiation. However, it is currently unknown whether additional radiosensitization could occur in the more clinically relevant setting of chemoradiation (CRT). We used the potent HSP90 inhibitor ganetespib to determine whether it can enhance CRT effects in NSCLC.. We first performed in vitro experiments in various NSCLC cell lines combining radiation with or without ganetespib. Some of these experiments included clonogenic survival assay, DNA damage repair, and cell-cycle analysis, and reverse-phase protein array. We then determined whether chemotherapy affected ganetespib radiosensitization by adding carboplatin-paclitaxel to some of the in vitro and in vivo xenograft experiments.. Ganetespib significantly reduced radiation clonogenic survival in a number of lung cancer cell lines, and attenuated DNA damage repair with irradiation. Radiation caused G. Ganetespib was able to potently sensitize a number of NSCLC cell lines to radiation but has variable effects when added to platinum-based doublet CRT. For optimal clinical translation, our data emphasize the importance of preclinical testing of drugs in the context of clinically relevant therapy combinations. Clin Cancer Res; 22(23); 5876-86. ©2016 AACR.

Topics: A549 Cells; Animals; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Chemoradiotherapy; Female; HSP90 Heat-Shock Proteins; Humans; Lung Neoplasms; Mice; Mice, Nude; Paclitaxel; Radiation-Sensitizing Agents; Triazoles; Xenograft Model Antitumor Assays

Small molecule inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase activity, such as erlotinib and gefitinib, revolutionized therapy for non-small cell lung cancer (NSCLC) patients whose tumors harbor activating EGFR mutations. However, mechanisms to overcome the invariable development of acquired resistance to such agents, as well as realizing their full clinical potential within the context of wild-type EGFR (WT-EGFR) disease, remain to be established. Here, the antitumor efficacy of targeted EGFR tyrosine kinase inhibitors (TKIs) and the HSP90 inhibitor ganetespib, alone and in combination, were evaluated in NSCLC. Ganetespib potentiated the efficacy of erlotinib in TKI-sensitive, mutant EGFR-driven NCI-HCC827 xenograft tumors, with combination treatment causing significant tumor regressions. In erlotinib-resistant NCI-H1975 xenografts, concurrent administration of ganetespib overcame erlotinib resistance to significantly improve tumor growth inhibition. Ganetespib co-treatment also significantly enhanced antitumor responses to afatinib in the same model. In WT-EGFR cell lines, ganetespib potently reduced cell viability. In NCI-H1666 cells, ganetespib-induced loss of client protein expression, perturbation of oncogenic signaling pathways, and induction of apoptosis translated to robust single-agent activity in vivo. Dual ganetespib/erlotinib therapy induced regressions in NCI-H322 xenograft tumors, indicating that the sensitizing properties of ganetespib for erlotinib were conserved within the WT-EGFR setting. Mechanistically, combined ganetespib/erlotinib exposure stabilized EGFR protein levels in an inactive state and completely abrogated extracellular-signal-regulated kinase (ERK) and AKT signaling activity. Thus, selective HSP90 blockade by ganetespib represents a potentially important complementary strategy to targeted TKI inhibition alone for inducing substantial antitumor responses and overcoming resistance, in both the mutant and WT-EGFR settings.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Synergism; ErbB Receptors; Female; HSP90 Heat-Shock Proteins; Humans; Lung Neoplasms; Mice, SCID; Mutation; Protein Kinase Inhibitors; Signal Transduction; Time Factors; Triazoles; Tumor Burden; Xenograft Model Antitumor Assays

Despite the common usage of radiotherapy for the treatment of NSCLC, outcomes for these cancers when treated with ionizing radiation (IR) are still unsatisfactory. A better understanding of the mechanisms underlying resistance to IR is needed to design approaches to eliminate the radioresistant cells and prevent tumor recurrence and metastases. Using multiple fractions of IR we generated radioresistant cells from T2821 and T2851 human lung adenocarcinoma cells. The radioresistant phenotypes present in T2821/R and T2851/R cells include multiple changes in DNA repair genes and proteins expression, upregulation of EMT markers, alterations of cell cycle distribution, upregulation of PI3K/AKT signaling and elevated production of growth factors, cytokines, important for lung cancer progression, such as IL-6, PDGFB and SDF-1 (CXCL12). In addition to being radioresistant these cells were also found to be resistant to cisplatin.HSP90 is a molecular chaperone involved in stabilization and function of multiple client proteins implicated in NSCLC cell survival and radioresistance. We examined the effect of ganetespib, a novel HSP90 inhibitor, on T2821/R and T2851/R cell survival, migration and radioresistance. Our data indicates that ganetespib has cytotoxic activity against parental T2821 and T2851 cells and radioresistant T2821/R and T2851/R lung tumor cells. Ganetespib does not affect proliferation of normal human lung fibroblasts. Combining IR with ganetespib completely abrogates clonogenic survival of radioresistant cells.Our data show that HSP90 inhibition can potentiate the effect of radiotherapy and eliminate radioresistant and cisplatin -resistant residual cells, thus it may aid in reducing NSCLC tumor recurrence after fractionated radiotherapy.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cisplatin; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; HSP90 Heat-Shock Proteins; Humans; Lung Neoplasms; Phenotype; Radiation Tolerance; Radiation-Sensitizing Agents; Signal Transduction; Time Factors; Triazoles

Small cell lung cancer (SCLC) at advanced stage is considered an incurable disease. Despite good response to initial chemotherapy, the responses in SCLC patients with metastatic disease are of short duration and resistance inevitably occurs. Although several target-specific drugs have altered the paradigm of treatment for many other cancers, we have yet to witness a revolution of the same magnitude in SCLC treatment. Anthracyclines, such as doxorubicin, have definite activity in this disease, and ganetespib has shown promising activity in preclinical models but underwhelming activity as a single agent in SCLC patients. Using SCLC cell lines, we demonstrated that ganetespib (IC50: 31 nM) was much more potent than 17-allylamino-17-demethoxygeldanamycin (17-AAG), a geldanamycin derivative (IC50: 16 μM). Ganetespib inhibited SCLC cell growth via induction of persistent G2/M arrest and Caspase 3-dependent cell death. MTS assay revealed that ganetespib synergized with both doxorubicin and etoposide, two topoisomerase II inhibitors commonly used in SCLC chemotherapy. Expression of receptor-interacting serine/threonine-protein kinase 1 (RIP1), a protein that may function as a pro-survival scaffold protein or a pro-death kinase in TNFR1-activated cells, was induced by doxorubicin and downregulated by ganetespib. Depletion of RIP1 by either RIP1 small interfering RNA (siRNA) or ganetespib sensitized doxorubicin-induced cell death, suggesting that RIP1 may promote survival in doxorubicin-treated cells and that ganetespib may synergize with doxorubicin in part through the downregulation of RIP1. In comparison to ganetespib or doxorubicin alone, the ganetespib+doxorubicin combination caused significantly more growth regression and death of human SCLC xenografts in immunocompromised mice. We conclude that ganetespib and doxorubicin combination exhibits significant synergy and is efficacious in inhibiting SCLC growth in vitro and in mouse xenograft models. Our preclinical study suggests that ganetespib and doxorubicin combination therapy may be an effective strategy for SCLC treatment, which warrants clinical testing.

Topics: Animals; Antibiotics, Antineoplastic; Cell Line, Tumor; Cell Survival; Doxorubicin; Drug Synergism; G2 Phase Cell Cycle Checkpoints; HSP90 Heat-Shock Proteins; Humans; Inhibitory Concentration 50; Lung Neoplasms; Mice; Mice, Nude; Small Cell Lung Carcinoma; Triazoles; Tumor Burden; Xenograft Model Antitumor Assays

Treatment options for patients with triple-negative breast cancer (TNBC) are largely limited to systemic chemotherapies, which have shown disappointing efficacy in the metastatic setting. Here, we undertook a comprehensive evaluation of the activity of ganetespib, a potent inhibitor of HSP90, in this malignancy.. The antitumor and antimetastatic activity of ganetespib was investigated using TNBC cell lines and xenograft models. Combinatorial drug analyses were performed with chemotherapeutic agents and concomitant effects on DNA damage and cell-cycle disruption were assessed in vitro; antitumor efficacy was assessed in vivo. Metabolic and objective tumor responses were evaluated in patients with metastatic TNBC undergoing ganetespib treatment.. Ganetespib simultaneously deactivated multiple oncogenic pathways to potently reduce cell viability in TNBC cell lines, and suppressed lung metastases in experimental models. Ganetespib potentiated the cytotoxic activity of doxorubicin via enhanced DNA damage and mitotic arrest, conferring superior efficacy to the doxorubicin-cyclophosphamide regimen in TNBC xenografts. Ganetespib also promoted mitotic catastrophe and apoptosis in combination with taxanes in vitro, and these effects translated to significantly improved combinatorial activity in vivo. Marked tumor shrinkage of metastatic lung and lymphatic lesions were seen in patients on ganetespib monotherapy.. The preclinical activity profile and clinical evidence of tumor regression suggest that ganetespib offers considerable promise as a new therapeutic candidate to target TNBC.

Topics: Animals; Antineoplastic Agents; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Disease Models, Animal; DNA Damage; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Drug Synergism; Female; HSP90 Heat-Shock Proteins; Humans; Lung Neoplasms; Mice; Mitosis; Neoplasm Metastasis; Neoplasm Staging; Positron-Emission Tomography; Tomography, X-Ray Computed; Triazoles; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Because of their pleiotropic effects on critical oncoproteins, inhibitors of HSP90 represent a promising new class of therapeutic agents for the treatment of human cancer. However, pharmacologic inactivation of HSP90 subsequently triggers a heat shock response that may mitigate the full therapeutic benefit of these compounds. To overcome this limitation, a clinically feasible method was sought to block HSP synthesis induced by the potent HSP90 inhibitor ganetespib. An immunoassay screen of 322 late-stage or clinically approved drugs was performed to uncover compounds that could block upregulation of the stress-inducible HSP70 that results as a consequence of HSP90 blockade. Interestingly, inhibitors of the phosphoinositide 3-kinase (PI3K)/mTOR class counteracted ganetespib-induced HSP70 upregulation at both the gene and protein level by suppressing nuclear translocation of heat shock factor 1 (HSF1), the dominant transcription factor controlling cellular stress responses. This effect was conserved across multiple tumor types and was found to be regulated, in part, by mTOR-dependent translational activity. Pretreatment with cycloheximide, PI3K/mTOR inhibitor, or an inhibitor of eIF4E (a translation initiation factor and downstream effector of mTOR) all reduced ganetespib-mediated nuclear HSF1 accumulation, indicating that mTOR blockade confers a negative regulatory effect on HSF1 activity. Moreover, combined therapy regimens with mTOR or dual PI3K/mTOR inhibitors potentiated the antitumor efficacy of ganetespib in multiple in vivo models.. Collectively these data identify a novel strategy to optimize the therapeutic potential of HSP90 inhibitors.

Topics: Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Female; Heat-Shock Response; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Lung Neoplasms; Male; Mice; Mice, SCID; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Random Allocation; Signal Transduction; TOR Serine-Threonine Kinases; Triazoles; Up-Regulation; Xenograft Model Antitumor Assays

Alectinib is a new generation ALK inhibitor with activity against the gatekeeper L1196M mutation that showed remarkable activity in a phase I/II study with echinoderm microtubule associated protein-like 4 (EML4)--anaplastic lymphoma kinase (ALK) non-small cell lung cancer (NSCLC) patients. However, alectinib resistance may eventually develop. Here, we found that EGFR ligands and HGF, a ligand of the MET receptor, activate EGFR and MET, respectively, as alternative pathways, and thereby induce resistance to alectinib. Additionally, the heat shock protein 90 (Hsp90) inhibitor suppressed protein expression of ALK, MET, EGFR, and AKT, and thereby induced apoptosis in EML4-ALK NSCLC cells, even in the presence of EGFR ligands or HGF. These results suggest that Hsp90 inhibitors may overcome ligand-triggered resistance to new generation ALK inhibitors and may result in more successful treatment of NSCLC patients with EML4-ALK.

Topics: Benzoquinones; Blotting, Western; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Epidermal Growth Factor; ErbB Receptors; Hepatocyte Growth Factor; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Ligands; Lung Neoplasms; Mutation; Oncogene Proteins, Fusion; Phosphorylation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Transforming Growth Factor alpha; Triazoles

A randomized phase II clinical trial demonstrated that combining the second-generation heat shock protein 90 inhibitor ganetespib with docetaxel can boost overall survival in patients with advanced lung adenocarcinoma who started therapy more than six months after diagnosis.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; HSP90 Heat-Shock Proteins; Humans; Lung Neoplasms; Neoplasm Staging; Randomized Controlled Trials as Topic; Survival Analysis; Taxoids; Triazoles; Xenograft Model Antitumor Assays

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Docetaxel; Erlotinib Hydrochloride; Female; Humans; Imidazoles; Indoles; Lung Neoplasms; Male; Medical Oncology; Multicenter Studies as Topic; Oximes; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Quinazolines; Randomized Controlled Trials as Topic; Small Cell Lung Carcinoma; Societies, Medical; Sulfones; Sunitinib; Taxoids; Treatment Outcome; Triazoles; United States

We describe the anticancer activity of ganetespib, a novel non-geldanamycin heat shock protein 90 (HSP90) inhibitor, in non-small cell lung cancer (NSCLC) models.. The activity of ganetespib was compared with that of the geldanamycin 17-AAG in biochemical assays, cell lines, and xenografts, and evaluated in an ERBB2 YVMA-driven mouse lung adenocarcinoma model.. Ganetespib blocked the ability of HSP90 to bind to biotinylated geldanamycin and disrupted the association of HSP90 with its cochaperone, p23, more potently than 17-AAG. In genomically defined NSCLC cell lines, ganetespib caused depletion of receptor tyrosine kinases, extinguishing of downstream signaling, inhibition of proliferation and induction of apoptosis with IC(50) values ranging 2 to 30 nmol/L, substantially lower than those required for 17-AAG (20-3,500 nmol/L). Ganetespib was also approximately 20-fold more potent in isogenic Ba/F3 pro-B cells rendered IL-3 independent by expression of EGFR and ERBB2 mutants. In mice bearing NCI-H1975 (EGFR L858R/T790M) xenografts, ganetespib was rapidly eliminated from plasma and normal tissues but was maintained in tumor with t(1/2) 58.3 hours, supporting once-weekly dosing experiments, in which ganetespib produced greater tumor growth inhibition than 17-AAG. However, after a single dose, reexpression of mutant EGFR occurred by 72 hours, correlating with reversal of antiproliferative and proapoptotic effects. Consecutive day dosing resulted in xenograft regressions, accompanied by more sustained pharmacodynamic effects. Ganetespib also showed activity against mouse lung adenocarcinomas driven by oncogenic ERBB2 YVMA.. Ganetespib has greater potency than 17-AAG and potential efficacy against several NSCLC subsets, including those harboring EGFR or ERBB2 mutation.

Topics: Animals; Antineoplastic Agents; Benzoquinones; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Female; HSP90 Heat-Shock Proteins; Humans; Intramolecular Oxidoreductases; Lactams, Macrocyclic; Lung Neoplasms; Mice; Mice, SCID; Prostaglandin-E Synthases; Protein Binding; Protein Stability; Triazoles; Xenograft Model Antitumor Assays

Mutant KRAS is a feature of more than 25% of non-small cell lung cancers (NSCLC) and represents one of the most prevalent oncogenic drivers in this disease. NSCLC tumors with oncogenic KRAS respond poorly to current therapies, necessitating the pursuit of new treatment strategies. Targeted inhibition of the molecular chaperone Hsp90 results in the coordinated blockade of multiple oncogenic signaling pathways in tumor cells and has thus emerged as an attractive avenue for therapeutic intervention in human malignancies. Here, we examined the activity of ganetespib, a small-molecule inhibitor of Hsp90 currently in clinical trials for NSCLCs in a panel of lung cancer cell lines harboring a diverse spectrum of KRAS mutations. In vitro, ganetespib was potently cytotoxic in all lines, with concomitant destabilization of KRAS signaling effectors. Combinations of low-dose ganetespib with MEK or PI3K/mTOR inhibitors resulted in superior cytotoxic activity than single agents alone in a subset of mutant KRAS cells, and the antitumor efficacy of ganetespib was potentiated by cotreatment with the PI3K/mTOR inhibitor BEZ235 in A549 xenografts in vivo. At the molecular level, ganetespib suppressed activating feedback signaling loops that occurred in response to MEK and PI3K/mTOR inhibition, although this activity was not the sole determinant of combinatorial benefit. In addition, ganetespib sensitized mutant KRAS NSCLC cells to standard-of-care chemotherapeutics of the antimitotic, topoisomerase inhibitor, and alkylating agent classes. Taken together, these data underscore the promise of ganetespib as a single-agent or combination treatment in KRAS-driven lung tumors.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Female; Genes, ras; Humans; Imidazoles; Lung Neoplasms; Mice; Mice, Nude; Mutation; Phosphoinositide-3 Kinase Inhibitors; Quinolines; Signal Transduction; TOR Serine-Threonine Kinases; Triazoles; Xenograft Model Antitumor Assays