scholarly journals GSK-3 Inhibition is Cytotoxic in Glioma Stem Cells through Centrosome Destabilization and Enhances the Effect of Radiotherapy in Orthotopic Models

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5939
Author(s):  
Anke Brüning-Richardson ◽  
Gary C. Shaw ◽  
Daniel Tams ◽  
Tim Brend ◽  
Hitesh Sanganee ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cytotoxic Effect ◽  
Glycogen Synthase ◽  
Combined Treatment ◽  
Single Agent ◽  
Drug Uptake ◽  
Growth Delay ◽  
Cancer Models ◽  
Established Cell

Background: Previous data on glycogen synthase kinase 3 (GSK-3) inhibition in cancer models support a cytotoxic effect with selectivity for tumor cells compared to normal tissue but the effect of these inhibitors in glioma has not been widely studied. Here, we investigate their potential as cytotoxics in glioma. Methods: We assessed the effect of pharmacologic GSK-3 inhibition on established (U87, U251) and patient-derived (GBM1, GBM4) glioblastoma (GBM) cell lines using cytotoxicity assays as well as undertaking a detailed investigation of the effect on cell cycle, mitosis, and centrosome biology. We also assessed drug uptake and efficacy of GSK-3 inhibition alone and in combination with radiation in xenograft models. Results: Using the selective GSK-3 inhibitor AZD2858, we demonstrated single agent cytotoxicity in two patient-derived glioma cell lines (GBM1, GBM4) and two established cell lines (U251 and U87) with IC50 in the low micromolar range promoting centrosome disruption, failed mitosis, and S-phase arrest. Glioma xenografts exposed to AZD2858 also showed growth delay compared to untreated controls. Combined treatment with radiation increased the cytotoxic effect of clinical radiation doses in vitro and in orthotopic glioma xenografts. Conclusions: These data suggest that GSK-3 inhibition promotes cell death in glioma through disrupting centrosome function and promoting mitotic failure and that AZD2858 is an effective adjuvant to radiation at clinical doses.

Tandutinib (MLN518), a Potent FLT3 Inhibitor, Synergizes with Cytarabine and/or Daunorubicin in a Sequence-Independent Manner.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1374-1374 ◽  
Author(s):  
Marcus M. Schittenhelm ◽  
Kevin W. Yee ◽  
Kerstin M. Kampa ◽  
Michael C. Heinrich
Keyword(s):  
Combination Therapy ◽  
Synergistic Effect ◽  
Cell Lines ◽  
Induction Chemotherapy ◽  
Combined Treatment ◽  
Single Agent ◽  
Cytotoxic Agents ◽  
Comparable Efficacy ◽  
Flt3 Inhibitor

Abstract FLT3 kinase inhibitors display promising pre-clinical efficacy in a variety of in vitro and animal models of FLT3-ITD+ AML. Tandutinib is a 4-piprazinylquinazoline compound that is a potent inhibitor of type III RTKs with a cellular IC50 of ~200 nM for FLT3. In a phase 2 study, Tandutinib demonstrated anti-leukemic activity in approximately half of the evaluable patients, although there were no partial or complete remissions. Therefore, optimal use of like Tandutinib will likely require combination therapy with standard cytotoxic agents such as cytarabine (Cy) and an anthracycline (e.g. daunorubicin, Dn). Notably, single agent Tandutinib has not been associated with myelosuppression, mucositis or cardiac toxicity--the dose limiting toxicities of AML chemotherapy. To determine the feasibility of combining Tandutinib and chemotherapy, we tested Tandutinib in combination with Cy and/or Dn. For our experiments, we utilized three cell lines containing FLT3 ITD mutations: a BaF3 cell line transduced with an ITD mutant FLT3 as well as MV 4–11 and MOLM 14 cell lines which have naturally occurring FLT3 ITD mutations. Data was analyzed using the statistical methods of Chou and Talalay to calculate combination indices (CI) for drug mixtures performed in a fixed dilution pattern. In all cell lines, calculated combination indices for inhibition of cellular proliferation and induction of apoptosis were much less than one, indicating a synergistic effect of combining Tandutinib with Cy or Dn. In addition, the combination of Tandutinib with Cy and Dn was also markedly synergistic. These results were confirmed using primary AML blasts (FLT3 ITD+). All of the above studies were performed using simultaneous treatment with Tandutinib and Cy and/or Dn. Previous in vitro studies utilizing a structurally unrelated FLT3 inhibitor, Lestaurtinib (CEP-701), demonstrated the potential importance of treatment sequencing for optimal killing of AML cells. Notably, treatment with Lestaurtinib with or following chemotherapy was found to be synergistic, whereas treatment with Lestaurtinib followed by chemotherapy was generally antagonistic. Therefore, we next determined whether sequencing of Tandutinib and chemotherapy had any effect on the efficacy of combination therapy. For these experiments, we tested two different sequencing regimens: monotherapy treatment with Tandutinib for 24 hours with the addition of Cy or Dn for an additional 48 hours; ormonotherapy with Cy or Dn for 24 hours with the addition of Tandutinib for an additional 48 hours. Both regimens produced a synergistic effect and had comparable efficacy. Therefore, unlike Lestaurtinib, the synergistic effect of Tandutinib and Cy/Dn appears to be independent of the sequence of drug administration. These data suggest that addition of Tandutinib to agents used in induction chemotherapy for AML could result in enhanced antileukemic effects. Our synergy experiments also suggest that combined use of Tandutinib and chemotherapy may allow dose reduction of chemotherapy (with resultant decreased side effects) without loss of antileukemic activity. Such a combined treatment approach may be particularly desirable for elderly AML patients who often have poor tolerance of standard AML chemotherapy regimens. Currently, the combination of Tandutinib + standard induction chemotherapy is being tested in a phase I/II study for treatment of newly diagnosed AML.

Small molecule pan-bcl-2 inhibitor AT-101 induces apoptosis in NSCLC by up-regulating noxa and enhances antitumor activity of docetaxel or targeted kinase inhibitors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14591-e14591
Author(s):  
P. Min ◽  
Y. Zhang ◽  
X. Ni ◽  
H. Wang ◽  
J. Wang ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Kinase Inhibitors ◽  
Combined Treatment ◽  
Single Agent ◽  
A549 Cells ◽  
Growth Delay ◽  
Phase Ii Trials ◽  
Xenograft Models

e14591 Background: AT-101 is an orally active pan Bcl-2 inhibitor currently under clinical development in Phase II trials. We investigated the effect of AT-101 alone or in combination with chemotherapies or targeted kinase inhibitors in NSCLC both in vitro and in vivo. Methods: Growth inhibition was measured by WST assays. The CalculSyn method was used to assess drug interaction by calculating the Combination Index (CI) value. The ability of AT-101 to potentiate the anti-cancer effect of chemotherapies or kinase inhibitors was evaluated in xenograft models. Results: A panel of 11 NSCLC cell lines with overexpression of Bcl-2, Bcl- XL or Mcl-1 proteins was treated with AT-101, docetaxel, pemetrexed, erlotinib, sorafenib, sunitinib, rapamycin, as a single agent and in combination. AT-101 inhibited the growth with IC50 at 3–9 uM. When treating cells simultaneously with both agents, AT-101 demonstrated strong synergy with those agents in A549 or H460 cells with CI values < 1.0. Protein analysis results indicated that AT-101 caused apoptosis by a time- and dose-dependent induction of Noxa expression in those cells. The expression of Bcl- XL was not influenced by AT-101. Pro-Caspase-3 was reduced with increasing doses of AT-101. In vivo, combined treatment of AT-101 with docetaxel, erlotinib, or sorafenib synergistically suppressed subcutaneous NSCLC A549 cells tumor growth compared with treatment with either agent alone. The synergist effects with the ErbB1 inhibitor Erlotinib is associated with the overexpression of the target protein ErbB1 in those cells. Only combination therapy resulted in significant tumor growth delay and no significant toxicities were observed. Conclusions: Our results demonstrate that AT-101significantly enhances the anti-tumor activity of chemotherapy and targeted agents and may represent a promising new anticancer agent with a novel molecular mechanism. Molecular targeted therapy with AT-101 may improve the outcome of current chemotherapy for NSCLC with Bcl-2, Bcl-xL and/or Mcl-1 overexpression. [Table: see text]

Primary glioblastoma cell lines as source for analysis of the relationship between molecular phenotype and in-vitro drug sensitivity.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13053-e13053
Author(s):  
Carl Friedrich Classen ◽  
Christina S Mullins ◽  
Julia Schubert ◽  
Piek Jürgen ◽  
Michael Linnebacher ◽  
...  
Keyword(s):  
Cell Lines ◽  
Drug Sensitivity ◽  
Combined Treatment ◽  
Single Agent ◽  
Response Analysis ◽  
Pathology Laboratory ◽  
In Vivo Models ◽  
Molecular Features

e13053 Background: Glioblastoma multiforma (GBM) still has a very poor prognosis even with today’s multimodal combination therapy of resection followed by radio-chemotherapy with temozolomide. Both new molecular inhibitors and immunotherapy may represent future therapeutical tools but due to the variability of the molecular composition in individual GBM, they probably depend on better response prediction. Methods: Based on a close cooperation and logistics between surgery, pathology, laboratory researchers and animal care facilities, we established and analysed cell lines of about 30 primary brain tumors, most of them GBM. Tumors and cell lines were characterised by morphology, growth behaviour, numerous extra- and intracellular antigens, and particularly regarding molecular features. Further, tumors were established in a subcutaneous xenograft mouse model, and growth characteristics were described. These in vitro and in vivo models represent an ideal tool for response analysis of single agent or combined treatment in early cell passages in order to predict response. Besides, relevant antigens and possible shifts of antigen-presentation in tumors can be assessed. Numerous analyses using established and new antitumor compounds – e.g. the integrin inhibitor cilengitide – were performed. Results: We found that although the specific integrin expression is individually different in the tumors analysed, cilengitide sensitivity was similar in most. Addition of temozolomide led to additional, yet not over-additive cytotoxicity. In our panel of GBM specimens we found a very heterogenous pattern of molecular alterations, going along with variations of drug sensitivity. Conclusions: This indicates that, in the future field of individualized approaches, such models are required, in order to enable future strategies to predict the efficacy of immunological, small molecular, biological-based, cytotoxic or other therapeutic strategies. The project was supported by the Förderkreis für krebskranke Kinder Rostock e.V., by a Mecklenburg-Vorpommern graduate scholarship, and by a cooperation with Merck-Serono Research and Development (gift of drug).

Relationship of EGFR-independent activation of PI3K in KRAS wild-type colorectal cancers and cetuximab resistance.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 385-385 ◽  
Author(s):  
Ryan Bruce Corcoran ◽  
Hiromichi Ebi ◽  
David P. Ryan ◽  
Jeffrey A. Meyerhardt ◽  
Jeffrey A. Engelman
Keyword(s):  
Cell Lines ◽  
Combined Treatment ◽  
Single Agent ◽  
Pi3k Pathway ◽  
Erk Signaling ◽  
Regulatory Subunit ◽  
Pi3k Activation ◽  
Xenograft Models ◽  
Pre Treatment

385 Background: Therapies targeting receptor tyrosine kinases (RTKs) are typically effective only when they lead to simultaneous inhibition of PI3K-AKT and MEK-ERK signaling. Cetuximab is a monoclonal antibody against EGFR that has been approved for treatment of metastatic colorectal cancer (CRC). Studies have suggested that its benefit is restricted to patients with KRAS wildtype (WT) CRC. However, even in KRAS WT CRC, the response rate to single-agent cetuximab is low, and the mechanistic basis for this is not well-understood. Methods: The ability of cetuximab to inhibit PI3K-AKT and MEK-ERK signaling in a panel of KRAS WT CRC cell lines was assessed by immunoblotting. Paired biopsies from CRC patients obtained pre-treatment and after 3 weeks of cetuximab were evaluated by immunohistochemistry and proteomic techniques to assess inhibition of PI3K activity. We preformed immunoprecipitations (IPs) of the regulatory subunit of PI3K from cell lines and primary CRCs to identify RTKs involved in PI3K activation. Cetuximab-based therapeutic combinations were evaluated in KRAS WT CRC cell lines and xenograft models. Results: Cetuximab led to effective inhibition of MEK-ERK signaling (>75% reduction in phospho-ERK), but led to incomplete inhibition of PI3K-AKT signaling (0-50% reduction in phospho-AKT) in all KRAS WT CRC cell lines tested. Analysis of paired biopsies from patients with KRAS WT CRC obtained pre-treatment and after 3 weeks of cetuximab demonstrated that the PI3K pathway remained active in many patients, despite cetuximab therapy. PI3K regulatory subunit IPs from cell lines and primary CRCs revealed multiple RTK inputs to PI3K, most notably from IGFIR. Combined treatment with cetuximab and an IGFIR inhibitor or a PI3K inhibitor led to improved efficacy in vitro and to tumor regressions in KRAS WT CRC xenograft models. Conclusions: Cetuximab fails to inhibit PI3K signaling in some KRAS WT CRCs. Additional RTKs other than EGFR play a role in PI3K activation in these cancers, which may contribute to cetuximab resistance. Combining cetuximab with targeted therapies directed against the PI3K pathway may lead to improved efficacy in KRAS WT CRC, and should be evaluated in future clinical trials.

Cytotoxic Effect of Brassica oleracea Extract on two Tumor Cell Lines in vitro

2013 ◽  
Vol 16 (1) ◽  
pp. 137-142
Author(s):  
Farooq I. Mohammed ◽  
◽  
Farah T. Abdullah ◽  
Shaimaa Y. Abdulfttah ◽  
◽  
...  
Keyword(s):  
Tumor Cell ◽  
Brassica Oleracea ◽  
Cell Lines ◽  
Cytotoxic Effect ◽  
Tumor Cell Lines

scholarly journals Aspirin enhances the therapeutic efficacy of cisplatin in oesophageal squamous cell carcinoma by inhibition of putative cancer stem cells

2021 ◽  
Author(s):  
Zhigeng Zou ◽  
Wei Zheng ◽  
Hongjun Fan ◽  
Guodong Deng ◽  
Shih-Hsin Lu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Squamous Cell Carcinoma ◽  
Cancer Stem Cells ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Squamous Cell ◽  
High Throughput Sequencing ◽  
Combined Treatment ◽  
Oesophageal Squamous Cell Carcinoma

Abstract Background Cancer stem cells (CSCs) are related to the patient’s prognosis, recurrence and therapy resistance in oesophageal squamous cell carcinoma (ESCC). Although increasing evidence suggests that aspirin (acetylsalicylic acid, ASA) could lower the incidence and improve the prognosis of ESCC, the mechanism(s) remains to be fully understood. Methods We investigated the role of ASA in chemotherapy/chemoprevention in human ESCC cell lines and an N-nitrosomethylbenzylamine-induced rat ESCC carcinogenesis model. The effects of combined treatment with ASA/cisplatin on ESCC cell lines were examined in vitro and in vivo. Sphere-forming cells enriched with putative CSCs (pCSCs) were used to investigate the effect of ASA in CSCs. Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) was performed to determine the alterations in chromatin accessibility caused by ASA in ESCC cells. Results ASA inhibits the CSC properties and enhances cisplatin treatment in human ESCC cells. ATAC-seq indicates that ASA treatment results in remarkable epigenetic alterations on chromatin in ESCC cells, especially their pCSCs, through the modification of histone acetylation levels. The epigenetic changes activate Bim expression and promote cell death in CSCs of ESCC. Furthermore, ASA prevents the carcinogenesis of NMBzA-induced ESCC in the rat model. Conclusions ASA could be a potential chemotherapeutic adjuvant and chemopreventive drug for ESCC treatment.

scholarly journals EPEN-33. PHARMACOGENOMICS REVEALS SYNERGISTIC INHIBITION OF ERBB2 AND PI3K SIGNALING AS A THERAPEUTIC STRATEGY FOR EPENDYMOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii314-iii314
Author(s):  
David Pauck ◽  
Eunice Paisana ◽  
Rita Cascão ◽  
Sevgi Sarikaya-Seiwert ◽  
Viktoria Marquardt ◽  
...  
Keyword(s):  
Primary Cultures ◽  
Single Agent ◽  
Pediatric Brain Tumor ◽  
Pediatric Brain Tumors ◽  
Primary Diagnosis ◽  
High Throughput Drug Screening ◽  
Established Cell ◽  
Set Up ◽  
Pediatric Brain

Abstract Subgroups of ependymoma, especially RELA fusion-positive and posterior fossa type A tumors, are associated with poor prognosis. Curative therapeutic strategies have not yet been identified. We set up a high-throughput drug screening (HTS) pipeline to evaluate clinically established compounds (n=196) in primary ependymoma cultures (n=12). As culturing ependymoma is challenging, assay miniaturization to 1536-well microplates emerged as a key feature to process HTS despite smallest cell numbers. DNA methylation profiling showed that entity and subgroup affiliation from primary diagnosis was maintained in primary cultures, as assessed through molecular neuropathology 2.0 based classification (MNP 2.0, Capper, D. et al., Nature, 2018). A comparison of HTS data of ependymoma and other pediatric brain tumor models (n=48) revealed a remarkable chemoresistance in vitro. However, we identified Neratinib, an irreversible ERBB2 inhibitor, as the most prominent candidate which was preferentially active in a subset of the investigated ependymoma cultures (n=5). Combinatory treatment with Copanlisib, a PI3K inhibitor, was able to overcome resistance to single agent treatment using Neratinib in established cell lines of ependymoma (n=3) and 2/4 primary cultures for which combinatory treatment could be tested. Finally, we validated efficacy of Neratinib combined with Copanlisib in mice bearing ependymoma xenografts which revealed significantly reduced tumor size compared to vehicle-treated animals. In summary, our study demonstrates that HTS may reveal targeted therapies for pediatric brain tumors. Specifically, we found a synergistic interaction of Neratinib and Copanlisib for treatment of ependymoma, thereby providing a novel therapeutic approach in an otherwise largely chemoresistant entity.

P04.20 The role of YAP in Glioblastoma cell lines

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii22-ii23
Author(s):  
G Casati ◽  
L Giunti ◽  
A Iorio ◽  
A Marturano ◽  
I Sardi
Keyword(s):  
Cell Viability ◽  
Cell Lines ◽  
Western Blotting ◽  
Cytotoxic Effect ◽  
Target Genes ◽  
Hippo Pathway ◽  
Combined Treatment ◽  
Set Up ◽  
The Hippo Pathway

Abstract BACKGROUND Glioblastoma (GBM) is a primary human malignant brain tumor, the most common in adults. Several studies have highlighted the Hippo-pathway as a cancer signalling network. The Hippo pathway is an evolutionarily conserved signal cascade, which is involved in the control of organ growth. Dysregulations among this pathway have been found in lung, ovarian, liver and colorectal cancer. The key downstream effector of the Hippo-pathway is the Yes-associated protein (YAP); in the nucleus, its function as transcription co-activator is to interact with transcription factors, resulting in the expression of target genes involved in pro-proliferating and anti-apoptotic programs. MATERIAL AND METHODS Using western blotting analysis, we determined the nuclear expression of YAP on three GBM cell lines (U87MG, T98G and A172). To investigate which inhibitors against the Hippo-pathway were the most efficient, we performed a cytotoxic assay: we treated all the three cell lines with different inhibitors such as Verteporfin (VP), Cytochalasin D (CIT), Latrunculin A (LAT), Dobutamine (DOB) and Y27632. Afterwards, we performed a treatment using Doxorubicin (DOX) combined with the inhibitors, evaluating its cytotoxic effect on our cell lines, through cell viability experiments. More western blotting experiments were performed to investigate the oncogenic role of YAP at nucleus level. Furthermore, preliminary experiments have been conducted in order to investigate the apoptosis, senescence and autophagy modulation due to the Hippo-pathway. RESULTS We showed our cell lines express nuclear YAP. We assessed the efficiency of the main inhibitors against Hippo-pathway, proving that VP, LAT A and CIT show a strong cytostatic effect, linked to time increase; plus we saw a cytotoxic effect on T98G. The association of DOX with selected inhibitors is able to reduce cell viability and nuclear YAP expression rate in all three GBM lines. Finally, preliminary experiments were set up to assess how and if the mechanisms of apoptosis, autophagy and senescence were affected by the Hippo-pathway. The combination of DOX with inhibitors promotes resistance to apoptosis. CONCLUSION Our results show that nuclear YAP is present in all tumor lines, thus confirming that this molecular pathway is functioning in GBM lines. Nuclear YAP is more highly expressed after DOX administration. Moreover, the combined treatment (DOX with Hippo-pathway inhibitors) reduces both cell proliferation and viability, and increases the rate of apoptosis. Preliminary experiments on senescence and autophagy were used to determine the best Hippo-pathway inhibitor. These data demonstrate that the Hippo-pathway plays a crucial role in GBM proliferation and resistance to apoptosis. Inhibiting this pathway and in particular the transcription factor YAP, in association with DOX, might be an excellent therapeutic target.

scholarly journals BET bromodomain inhibitor birabresib in mantle cell lymphoma: in vivo activity and identification of novel combinations to overcome adaptive resistance

ESMO Open ◽  
2018 ◽  
Vol 3 (6) ◽  
pp. e000387 ◽  
Author(s):  
Chiara Tarantelli ◽  
Elena Bernasconi ◽  
Eugenio Gaudio ◽  
Luciano Cascione ◽  
Valentina Restelli ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Antitumour Activity ◽  
Single Agent ◽  
Treatment Strategies ◽  
Bet Inhibitor ◽  
Mantle Cell

BackgroundThe outcome of patients affected by mantle cell lymphoma (MCL) has improved in recent years, but there is still a need for novel treatment strategies for these patients. Human cancers, including MCL, present recurrent alterations in genes that encode transcription machinery proteins and of proteins involved in regulating chromatin structure, providing the rationale to pharmacologically target epigenetic proteins. The Bromodomain and Extra Terminal domain (BET) family proteins act as transcriptional regulators of key signalling pathways including those sustaining cell viability. Birabresib (MK-8628/OTX015) has shown antitumour activity in different preclinical models and has been the first BET inhibitor to successfully undergo early clinical trials.Materials and methodsThe activity of birabresib as a single agent and in combination, as well as its mechanism of action was studied in MCL cell lines.ResultsBirabresib showed in vitro and in vivo activities, which appeared mediated via downregulation of MYC targets, cell cycle and NFKB pathway genes and were independent of direct downregulation of CCND1. Additionally, the combination of birabresib with other targeted agents (especially pomalidomide, or inhibitors of BTK, mTOR and ATR) was beneficial in MCL cell lines.ConclusionOur data provide the rationale to evaluate birabresib in patients affected by MCL.

scholarly journals Identification of Hsp90 inhibitors as potential drugs for the treatment of TSC1/TSC2 deficient cancer

2021 ◽  
Author(s):  
Evelyn M. Mrozek ◽  
Vineeta Bajaj ◽  
Yanan Guo ◽  
Izabela Malinowska ◽  
Jianming Zhang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Xenograft Model ◽  
Growth Delay ◽  
Hsp90 Inhibitors ◽  
Null Cell ◽  
Standard Dosage

Inactivating mutations in either TSC1 or TSC2 cause Tuberous Sclerosis Complex, an autosomal dominant disorder, characterized by multi-system tumor and hamartoma development. Mutation and loss of function of TSC1 and/or TSC2 also occur in a variety of sporadic cancers, and rapamycin and related drugs show highly variable treatment benefit in patients with such cancers. The TSC1 and TSC2 proteins function in a complex that inhibits mTORC1, a key regulator of cell growth, which acts to enhance anabolic biosynthetic pathways. In this study, we identified and validated five cancer cell lines with TSC1 or TSC2 mutations and performed a kinase inhibitor drug screen with 197 compounds. The five cell lines were sensitive to several mTOR inhibitors, and cell cycle kinase and HSP90 kinase inhibitors. The IC50 for Torin1 and INK128, both mTOR kinase inhibitors, was significantly increased in three TSC2 null cell lines in which TSC2 expression was restored.  Rapamycin was significantly more effective than either INK128 or ganetespib (an HSP90 inhibitor) in reducing the growth of TSC2 null SNU-398 cells in a xenograft model. Combination ganetespib-rapamycin showed no significant enhancement of growth suppression over rapamycin. Hence, although HSP90 inhibitors show strong inhibition of TSC1/TSC2 null cell line growth in vitro, ganetespib showed little benefit at standard dosage in vivo. In contrast, rapamycin which showed very modest growth inhibition in vitro was the best agent for in vivo treatment, but did not cause tumor regression, only growth delay.

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