title: Differential regulation of mTOR signaling determines sensitivity to AKT inhibition in diffuse large B cell lymphoma.
abstract: Agents that target components of the PI3K/AKT/mTOR pathway are under investigation for the treatment of diffuse large B cell lymphoma (DLBCL). Given the highly heterogeneous nature of DLBCL, it is not clear whether all subtypes of DLBCL will be susceptible to PI3K pathway inhibition, or which kinase within this pathway is the most favorable target. Pharmacological profiling of a panel of DLBCL cell lines revealed a subset of DLBCL that was resistant to AKT inhibition. Strikingly, sensitivity to AKT inhibitors correlated with the ability of these inhibitors to block phosphorylation of S6K1 and ribosomal protein S6. Cell lines resistant to AKT inhibition activated S6K1 independent of AKT either through upregulation of PIM2 or through activation by B cell receptor (BCR) signaling components. Finally, combined inhibition of AKT and BTK, PIM2, or S6K1 proved to be an effective strategy to overcome resistance to AKT inhibition in DLBCL.
authors.affiliation: AstraZeneca Oncology, Waltham, Massachusetts, MA, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Ezell
authors.affiliation: AstraZeneca Oncology, Waltham, Massachusetts, MA, USA.
authors.forename: Suping
authors.initials: S
authors.lastname: Wang
authors.affiliation: AstraZeneca Oncology, Waltham, Massachusetts, MA, USA.
authors.forename: Teeru
authors.initials: T
authors.lastname: Bihani
authors.affiliation: AstraZeneca Oncology, Waltham, Massachusetts, MA, USA.
authors.forename: Zhongwu
authors.initials: Z
authors.lastname: Lai
authors.affiliation: AstraZeneca Oncology, Waltham, Massachusetts, MA, USA.
authors.forename: Shaun E
authors.initials: SE
authors.lastname: Grosskurth
authors.affiliation: AstraZeneca Oncology, Waltham, Massachusetts, MA, USA.
authors.forename: Suprawee
authors.initials: S
authors.lastname: Tepsuporn
authors.affiliation: AstraZeneca Oncology, Macclesfield, Cheshire, UK.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Davies
authors.affiliation: AstraZeneca Oncology, Waltham, Massachusetts, MA, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Huszar
authors.affiliation: AstraZeneca Oncology, Waltham, Massachusetts, MA, USA.
authors.forename: Kate F
authors.initials: KF
authors.lastname: Byth
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D038601:Ribosomal Protein S6; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C490587:PIM2 protein, human; C546842:MTOR protein, human; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1
keywords: AKT; DLBCL; Ibrutinib; S6K1; mTOR
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