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AKT signaling mediates the cellular adaptation to LAT1 pharmacologic inhibition in pancreatic ductal adenocarcinoma.

ABSTRACT: To characterize the changes of phosphorylation signaling cascades induced by LAT1 inhibition in MIA PaCa-2 cells treated with LAT1 specific inhibitor JPH203, immobilized metal affinity chromatography and liquid chromatography-tandem mass spectrometry with MS2-based quantitation of tandem mass tag were utilized. To characterize the changes of protein expressions induced by LAT1 inhibition and AKT inhibition in MIA PaCa-2 cells exposed to LAT1 specific inhibitor JPH203 with or without AKT inhibitor MK-2206, immobilized metal affinity chromatography and liquid chromatography-tandem mass spectrometry with MS2-based quantitation of tandem mass tag were utilized.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Yoshikatsu Kanai

PROVIDER: PXD034389 | JPOST Repository | Mon Apr 15 00:00:00 BST 2024

REPOSITORIES: jPOST

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			Action	DRS
	20200521_Ma_MIA_JPH_1d_IMAC_TMT_01_5p.raw	Raw
	20200521_Ma_MIA_JPH_1d_IMAC_TMT_02_7p.raw	Raw
	20200521_Ma_MIA_JPH_1d_IMAC_TMT_03_9p.raw	Raw
	20200521_Ma_MIA_JPH_1d_IMAC_TMT_04_11p.raw	Raw
	20200521_Ma_MIA_JPH_1d_IMAC_TMT_05_13p.raw	Raw

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Project description:Purpose: Deregulated phosphatidylinositol 3-kinase pathway signaling through AGC kinases including AKT, p70S6 kinase, PKA, SGK and Rho kinase, is a key driver of multiple cancers. The simultaneous inhibition of multiple AGC kinases may increase antitumor activity and minimize clinical resistance compared with a single pathway component. Experimental Design: We investigated the detailed pharmacology and antitumor activity of the novel clinical drug candidate AT13148, an oral ATP-competitive multi-AGC kinase inhibitor. Gene expression microarray studies were undertaken to characterize the molecular mechanisms of action of AT13148. Results: AT13148 caused substantial blockade of AKT, p70S6K, PKA, ROCK and SGK substrate phosphorylation and induced apoptosis in a concentration and time-dependent manner in cancer cells with clinically relevant genetic defects in vitro and in vivo. Antitumor efficacy in HER2-positive, PIK3CA-mutant BT474 breast, PTEN-deficient PC3 human prostate cancer and PTEN-deficient MES-SA uterine tumor xenografts was demonstrated. We show for the first time that induction of AKT phosphorylation at serine 473 by AT13148, as reported for other ATP-competitive inhibitors of AKT, is not a therapeutically relevant reactivation step. Gene expression studies showed that AT13148 has a predominant effect on apoptosis genes, whereas the selective AKT inhibitor CCT128930 modulates cell cycle genes. Induction of upstream regulators including IRS2 and PIK3IP1 due to compensatory feedback loops was observed. Conclusions: The clinical candidate AT13148 is a novel oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity, which demonstrates a distinct mechanism of action from other AKT inhibitors. AT13148 will now be assessed in a first-in-human Phase I trial. The PTEN-deficient U87MG glioblastoma cell line was treated for 6 hours with vehicle control (DMSO) or to different concentrations of AT13148 and CCT128930 (0.1uM, 1xGI50 and 3XGI50).

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AKT signaling mediates the cellular adaptation to LAT1 pharmacologic inhibition in pancreatic ductal adenocarcinoma.

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