Pan-mTOR inhibitor MLN0128 is effective against intrahepatic cholangiocar- cinoma induced in mice by AKT and Yap co-expression

Background & Aims— Intrahepatic cholangiocarcinoma (ICC) is a lethal malignancy without effective treatment options. MLN0128, a second-generation pan-mTOR inhibitor, shows efficacy for multiple tumor types. Methods— We established a novel ICC mouse model via hydrodynamic transfection of activated forms of AKT (myr-AKT) and Yap (YapS127A) protooncogenes (that will be referred to as AKT/ YapS127A). Genetic approaches were applied to study the requirement of mTORC1 and mTORC2 in mediating AKT/YapS127A driven tumorigenesis. Gemcitabine/Oxaliplatin and MLN0128 were administered in AKT/YapS127A tumor-bearing mice to study their antitumor efficacy in vivo. Multiple human ICC cell lines were used for in vitro experiments. Hematoxylin and eosin staining, immunohistochemistry and immunoblotting were applied for characterization and mechanistic study. Results— Co-expression of myr-AKT and YapS127A promoted ICC development in mice. Both mTORC1 and mTORC2 complexes were required for AKT/YapS127A ICC development. Gemcitabine/Oxaliplatin had limited efficacy in treating late stage AKT/YapS127A ICC. In contrast, partial tumor regression was achieved when MLN0128 was applied in the late stage of AKT/YapS127A

[1]  D. Calvisi,et al.  Co-activation of AKT and c-Met triggers rapid hepatocellular carcinoma development via the mTORC1/FASN pathway in mice , 2016, Scientific Reports.

[2]  A. Bauer,et al.  YAP promotes proliferation, chemoresistance, and angiogenesis in human cholangiocarcinoma through TEAD transcription factors , 2015, Hepatology.

[3]  G. Gores,et al.  IL‐33 facilitates oncogene‐induced cholangiocarcinoma in mice by an interleukin‐6‐sensitive mechanism , 2015, Hepatology.

[4]  Jian Yu,et al.  mTOR inhibitors induce apoptosis in colon cancer cells via CHOP-dependent DR5 induction upon 4E-BP1 dephosphorylation , 2015, Oncogene.

[5]  Jeffrey W. Smith,et al.  4EBP1/eIF4E and p70S6K/RPS6 axes play critical and distinct roles in hepatocarcinogenesis driven by AKT and N‐Ras proto‐oncogenes in mice , 2015, Hepatology.

[6]  Elisa de Stanchina,et al.  MLN0128, an ATP-Competitive mTOR Kinase Inhibitor with Potent In Vitro and In Vivo Antitumor Activity, as Potential Therapy for Bone and Soft-Tissue Sarcoma , 2014, Molecular Cancer Therapeutics.

[7]  D. Calvisi,et al.  Activation of β-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice. , 2014, Gastroenterology.

[8]  G. Mills,et al.  Catalytic mTOR inhibitors can overcome intrinsic and acquired resistance to allosteric mTOR inhibitors , 2014, Oncotarget.

[9]  T. Pawlik,et al.  Hepatobiliary cancers, version 2.2014. , 2014, Journal of the National Comprehensive Cancer Network : JNCCN.

[10]  Patrick Cahan,et al.  Hippo Pathway Activity Influences Liver Cell Fate , 2014, Cell.

[11]  T. Pawlik,et al.  Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. , 2014, Journal of hepatology.

[12]  R. Nolley,et al.  Preclinical trial of a new dual mTOR inhibitor, MLN0128, using renal cell carcinoma tumorgrafts , 2014, International journal of cancer.

[13]  Jiri Polivka,et al.  Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. , 2014, Pharmacology & therapeutics.

[14]  D. Calvisi,et al.  Hydrodynamic transfection for generation of novel mouse models for liver cancer research. , 2014, The American journal of pathology.

[15]  C. Rommel,et al.  PI3K and cancer: lessons, challenges and opportunities , 2014, Nature Reviews Drug Discovery.

[16]  K. Shokat,et al.  Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers , 2013, Proceedings of the National Academy of Sciences.

[17]  R. Wells,et al.  Robust cellular reprogramming occurs spontaneously during liver regeneration. , 2013, Genes & development.

[18]  C. Rommel,et al.  Efficacy of the investigational mTOR kinase inhibitor MLN0128/INK128 in models of B-cell acute lymphoblastic leukemia , 2013, Leukemia.

[19]  D. Pincus,et al.  Endoplasmic reticulum stress sensing in the unfolded protein response. , 2013, Cold Spring Harbor perspectives in biology.

[20]  W. Palmer,et al.  Are common factors involved in the pathogenesis of primary liver cancers? A meta-analysis of risk factors for intrahepatic cholangiocarcinoma. , 2012, Journal of hepatology.

[21]  J. Baselga,et al.  Dual Mtorc1/2 and Her2 Blockade Results in Antitumor Activity in Preclinical Models of Breast Cancer Resistant to Anti-her2 Therapy Statement of Translational Relevance , 2022 .

[22]  D. Calvisi,et al.  AKT (v‐akt murine thymoma viral oncogene homolog 1) and N‐Ras (neuroblastoma ras viral oncogene homolog) coactivation in the mouse liver promotes rapid carcinogenesis by way of mTOR (mammalian target of rapamycin complex 1), FOXM1 (forkhead box M1)/SKP2, and c‐Myc pathways , 2012, Hepatology.

[23]  Nicholas T. Ingolia,et al.  The translational landscape of mTOR signalling steers cancer initiation and metastasis , 2012, Nature.

[24]  M. Hall,et al.  Rapamycin passes the torch: a new generation of mTOR inhibitors , 2011, Nature Reviews Drug Discovery.

[25]  X. Zheng,et al.  Targeting the mTOR kinase domain: the second generation of mTOR inhibitors. , 2011, Drug discovery today.

[26]  D. Calvisi,et al.  Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma. , 2011, Gastroenterology.

[27]  Pixu Liu,et al.  Targeting the phosphoinositide 3-kinase pathway in cancer , 2009, Nature Reviews Drug Discovery.

[28]  Seung‐Mo Hong,et al.  The Expression of Phospho-AKT, Phospho-mTOR, and PTEN in Extrahepatic Cholangiocarcinoma , 2009, Clinical Cancer Research.

[29]  K. Schmid,et al.  AKT and ERK1/2 signaling in intrahepatic cholangiocarcinoma. , 2007, World journal of gastroenterology.

[30]  N. Sonenberg,et al.  Upstream and downstream of mTOR. , 2004, Genes & development.

[31]  D. Stolz,et al.  Hydroporation as the mechanism of hydrodynamic delivery , 2004, Gene Therapy.

[32]  Hollis G. Potter,et al.  Author Manuscript , 2013 .