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IGF1 receptor inhib...
IGF1 receptor inhibition amplifies the effects of cancer drugs by autophagy and immune-dependent mechanisms
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Wu, Q (författare)
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Tian, AL (författare)
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Li, B (författare)
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Leduc, M (författare)
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Forveille, S (författare)
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Hamley, P (författare)
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Galloway, W (författare)
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Xie, W (författare)
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Liu, P (författare)
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Zhao, LW (författare)
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Zhang, S (författare)
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Hui, P (författare)
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Madeo, F (författare)
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Tu, Y (författare)
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Kepp, O (författare)
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Kroemer, G (författare)
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- 2021-06-14
- 2021
- Engelska.
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Ingår i: Journal for immunotherapy of cancer. - : BMJ. - 2051-1426. ; 9:6
- Relaterad länk:
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https://jitc.bmj.com...
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http://kipublication...
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https://doi.org/10.1...
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Abstract
Ämnesord
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- Pharmacological autophagy enhancement constitutes a preclinically validated strategy for preventing or treating most major age-associated diseases. Driven by this consideration, we performed a high-content/high-throughput screen on 65 000 distinct compounds on a robotized fluorescence microscopy platform to identify novel autophagy inducers.ResultsHere, we report the discovery of picropodophyllin (PPP) as a potent inducer of autophagic flux that acts on-target, as an inhibitor of the tyrosine kinase activity of the insulin-like growth factor-1 receptor (IGF1R). Thus, PPP lost its autophagy-stimulatory activity in cells engineered to lack IGF1R or to express a constitutively active AKT serine/threonine kinase 1 (AKT1) mutant. When administered to cancer-bearing mice, PPP improved the therapeutic efficacy of chemoimmunotherapy with a combination of immunogenic cytotoxicants and programmed cell death 1 (PDCD1, better known as PD-1) blockade. These PPP effects were lost when tumors were rendered PPP-insensitive or autophagy-incompetent. In combination with chemotherapy, PPP enhanced the infiltration of tumors by cytotoxic T lymphocytes, while reducing regulatory T cells. In human triple-negative breast cancer patients, the activating phosphorylation of IGF1R correlated with inhibited autophagy, an unfavorable local immune profile, and poor prognosis.ConclusionAltogether, these results suggest that IGF1R may constitute a novel and druggable therapeutic target for the treatment of cancer in conjunction with chemoimmunotherapies.
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- Av författaren/redakt...
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Wu, Q
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Tian, AL
-
Li, B
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Leduc, M
-
Forveille, S
-
Hamley, P
-
visa fler...
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Galloway, W
-
Xie, W
-
Liu, P
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Zhao, LW
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Zhang, S
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Hui, P
-
Madeo, F
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Tu, Y
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Kepp, O
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Kroemer, G
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visa färre...
- Artiklar i publikationen
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Journal for immu ...
- Av lärosätet
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Karolinska Institutet