The allosteric AKT inhibitor MK2206 shows a synergistic interaction with chemotherapy and radiotherapy in glioblastoma spheroid cultures

Narayan, Ravi S.; Fedrigo, Carlos Alexandre; Brands, Eelke; Dik, Rogier; Stalpers, Lukas J.A.; Baumert, Brigitta G.; Slotman, Ben J.; Westerman, Bart A.; Peters, Godefridus J.; Sminia, Peter

doi:10.1186/s12885-017-3193-9

Cited by 57 publications

(59 citation statements)

References 38 publications

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“…MEK1/2 inhibition by MEK162 enhances the effect of irradiation on U87 glioma spheroids We previously found that cell culture dimensionality profoundly influences the drug/radiotherapy interaction in glioma cells when pharmacologically inhibiting AKT (17) in agreement with earlier studies (18)(19)(20). Therefore, we chose to study the effect of a series of inhibitors of the PI3K and MAPK pathways in U87 glioma cells when cultured as 3D multicellular spheroids.…”

Section: Resultsmentioning

confidence: 56%

“…Therefore, we chose to study the effect of a series of inhibitors of the PI3K and MAPK pathways in U87 glioma cells when cultured as 3D multicellular spheroids. As reported previously, these inhibitors did not radiosensitize glioma cells when grown as a monolayer (17). We used similar culture techniques to maintain 3D structural integrity for a longer period of time (>40 days; see Materials and Methods).…”

Section: Resultsmentioning

confidence: 92%

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Identification of MEK162 as a Radiosensitizer for the Treatment of Glioblastoma

Narayan

Gasol

Slangen

et al. 2018

Molecular Cancer Therapeutics

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Glioblastoma (GBM) is a highly aggressive and lethal brain cancer type. PI3K and MAPK inhibitors have been studied preclinically in GBM as monotherapy, but not in combination with radiotherapy, which is a key component of the current standard treatment of GBM. In our study, GBM cell lines and patient representative primary cultures were grown as multicellular spheroids. Spheroids were treated with a panel of small-molecule drugs including MK2206, RAD001, BEZ235, MLN0128, and MEK162, alone and in combination with irradiation. Following treatment, spheroid growth parameters (growth rate, volume reduction, and time to regrow), cell-cycle distribution and expression of key target proteins were evaluated. , the effect of irradiation (3 × 2 Gy) without or with MEK162 (50 mg/kg) was studied in orthotopic GBM8 brain tumor xenografts with endpoints tumor growth and animal survival. The MAPK-targeting agent MEK162 was found to enhance the effect of irradiation as demonstrated by growth inhibition of spheroids. MEK162 downregulated and dephosphorylated the cell-cycle checkpoint proteins CDK1/CDK2/WEE1 and DNA damage response proteins p-ATM/p-CHK2. When combined with radiation, this led to a prolonged DNA damage signal. data on tumor-bearing animals demonstrated a significantly reduced growth rate, increased growth delay, and prolonged survival time. In addition, RNA expression of responsive cell cultures correlated to mesenchymal stratification of patient expression data. In conclusion, the MAPK inhibitor MEK162 was identified as a radiosensitizer in GBM spheroids and in orthotopic GBM xenografts The data are supportive for implementation of this targeted agent in an early-phase clinical study in GBM patients.

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Section: Resultsmentioning

confidence: 56%

Section: Resultsmentioning

confidence: 92%

Identification of MEK162 as a Radiosensitizer for the Treatment of Glioblastoma

Narayan

Gasol

Slangen

et al. 2018

Molecular Cancer Therapeutics

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“…For instance in several NSCLC models erlotinib increased the efficacy of pemetrexed [155] , while inhibition of AKT with perifosine enhanced the efficacy of the platinum analog satraplatin [156] . MK2206 enhanced the effect of radiation alone [157] or in combination with gemcitabine and radiation (El-Naggar, unpublished results). Unfortunately, the current AKT inhibitors (e.g., MK2206, perifosine) were not sufficiently effective in patients, but several novel inhibitors are under development.…”

Section: Future Directionsmentioning

confidence: 94%

Resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer

Steen¹,

Giovannetti²,

Carbone³

et al. 2018

CDR

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Aberrant activation of the epidermal growth factor receptor (EGFR) is a driving force for cancer growth in a subgroup of non-small cell lung cancer patients. These patients can be identified by the presence of activating EGFR mutations. Currently three generations of EGFR-tyrosine kinase inhibitors (TKIs) have been approved by the Food and Drug Administration and European Medicine Agency. This paper reviews the structure of EGFR and the downstream signaling pathways of EGFR and describes the mechanisms of intrinsic and acquired resistance against EGFR-TKIs. These mechanisms include secondary or tertiary mutations in EGFR, the activation of bypassing signaling pathways or a histological transformation to small cell lung cancer. Moreover, drug efflux transporters will affect the cellular accumulation of EGFR-TKIs and penetration of the first generation of EGFR-TKI into the brain. Lysosomal sequestration of some EGFR-TKIs may also prevent the drugs to reach their target. In conclusion, resistance to EGFR-TKIs is multifactorial, including primary and acquired mutations in the EGFR gene, activation of bypassing pathways and limited uptake of drugs in the cells or target tissues. More pharmacological studies are needed in order to develop new specific compounds targeted to overcome new resistance mechanisms in order to enable a personalized treatment approach.

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“…Fractional survival was then calculated as percentage to control cells. Data of combined drug effects were subsequently analyzed by the Chou and Talalay method [32,33] . Combination index (CoI) values < 1, = 1 and > 1 indicated synergism, additive effect and antagonism, respectively.…”

Section: Cell Viability Assaymentioning

confidence: 99%

PIM-1 inhibition with AZD1208 to prevent osimertinib-induced resistance in EGFR-mutation positive non-small cell lung cancer

Bracht¹,

Karachaliou²,

Berenguer³

et al. 2019

JCMT

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Aim: The progression free survival of non-small cell lung cancer (NSCLC) patients has been doubled over the last years, but still single epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) lead to incomplete responses. Compensatory signaling pathways are activated upon single EGFR TKIs. We have shown that compounds, which inhibit these pathways, are synergistic with EGFR TKIs. Proviral integration site for Moloney murine leukemia virus (PIM) has been connected to cancer therapy resistance, being involved in receptor tyrosine kinase, signal transducer and activator of transcription 3 (STAT3) and interleukin-6 signaling. We hypothesized that combined PIM and EGFR inhibition may improve the upfront therapy of EGFR-mutation positive NSCLC. Methods: We reviewed the literature on PIM kinases, and performed cell viability assays, gene expression analyses, and immunoblotting experiments to reveal the mechanisms of action of the PIM inhibitor (AZD1208) alone and combined with osimertinib in five EGFR-mutation positive NSCLC cell lines. Results: Osimertinib alone induced the activation of signal transducer and activator of transcription 3 (STAT3) as well as other signaling nodes. Combined osimertinib and AZD1208 yielded moderate synergistic effects in all NSCLC cell lines investigated. Among the EGFR-mutation positive cell lines examined, the H1975 and PC9 cell lines had the highest PIM1 and STAT3 mRNA expression. The combination decreased the osimertinib-induced STAT3 phosphorylation. Conclusion: This study provides a short review on PIM kinases, and shows our results of combined PIM and EGFR inhibition in EGFR-mutation positive NSCLC cell lines. The combination was moderately synergistic but decreased STAT3 phosphorylation, an important signaling node in therapy resistance.

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The allosteric AKT inhibitor MK2206 shows a synergistic interaction with chemotherapy and radiotherapy in glioblastoma spheroid cultures

Cited by 57 publications

References 38 publications

Identification of MEK162 as a Radiosensitizer for the Treatment of Glioblastoma

Identification of MEK162 as a Radiosensitizer for the Treatment of Glioblastoma

Resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer

PIM-1 inhibition with AZD1208 to prevent osimertinib-induced resistance in EGFR-mutation positive non-small cell lung cancer

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