PMID- 32747423 OWN - NLM STAT- MEDLINE DCOM- 20210806 LR - 20221019 IS - 1538-8514 (Electronic) IS - 1535-7163 (Print) IS - 1535-7163 (Linking) VI - 19 IP - 10 DP - 2020 Oct TI - Hypomorphic mTOR Downregulates CDK6 and Delays Thymic Pre-T LBL Tumorigenesis. PG - 2221-2232 LID - 10.1158/1535-7163.MCT-19-0671 [doi] AB - PI3K/AKT/mTOR pathway hyperactivation is frequent in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL). To model inhibition of mTOR, pre-T-cell lymphoblastic leukemia/lymphoma (pre-T LBL) tumor development was monitored in mice with T lymphocyte-specific, constitutively active AKT (Lck-MyrAkt2) that were either crossed to mTOR knockdown (KD) mice or treated with the mTOR inhibitor everolimus. Lck-MyrAkt2;mTOR KD mice lived significantly longer than Lck-MyrAkt2;mTOR wild-type (WT) mice, although both groups ultimately developed thymic pre-T LBL. An increase in survival was also observed when Lck-MyrAkt2;mTOR WT mice were treated for 8 weeks with everolimus. The transcriptional profiles of WT and KD thymic lymphomas were compared, and Ingenuity Pathway Upstream Regulator Analysis of differentially expressed genes in tumors from mTOR WT versus KD mice identified let-7 and miR-21 as potential regulatory genes. mTOR KD mice had higher levels of let-7a and miR-21 than mTOR WT mice, and rapamycin induced their expression in mTOR WT cells. CDK6 was one of the most downregulated targets of both let-7 and miR21 in mTOR KD tumors. CDK6 overexpression and decreased expression of let-7 in mTOR KD cells rescued a G(1) arrest phenotype. Combined mTOR (rapamycin) and CDK4/6 (palbociclib) inhibition decreased tumor size and proliferation in tumor flank transplants, increased survival in an intravenous transplant model of disseminated leukemia compared with single agent treatment, and cooperatively decreased cell viability in human T-ALL/LBL cell lines. Thus, mTOR KD mice provide a model to explore drug combinations synergizing with mTOR inhibitors and can be used to identify downstream targets of inhibition. CI - (c)2020 American Association for Cancer Research. FAU - Gary, Joy M AU - Gary JM AD - Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland. AD - Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan. FAU - Simmons, John K AU - Simmons JK AD - Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland. FAU - Xu, Jinfei AU - Xu J AD - Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania. FAU - Zhang, Shuling AU - Zhang S AD - Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland. FAU - Peat, Tyler J AU - Peat TJ AD - Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland. FAU - Watson, Nicholas AU - Watson N AD - Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland. FAU - Gamache, Benjamin J AU - Gamache BJ AD - Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland. AD - American University, Washington, DC. FAU - Zhang, Ke AU - Zhang K AD - Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland. FAU - Kovalchuk, Alexander L AU - Kovalchuk AL AD - Laboratory of Immunogenetics, NIAID, NIH, Rockville, Maryland. FAU - Michalowski, Aleksandra M AU - Michalowski AM AUID- ORCID: 0000-0001-9259-6101 AD - Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland. FAU - Chen, Jin-Qiu AU - Chen JQ AD - Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland. FAU - Thaiwong, Tuddow AU - Thaiwong T AD - Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan. FAU - Kiupel, Matti AU - Kiupel M AUID- ORCID: 0000-0003-4429-9529 AD - Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan. FAU - Gaikwad, Snehal AU - Gaikwad S AD - Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland. FAU - Etienne, Maudeline AU - Etienne M AD - Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland. FAU - Simpson, R Mark AU - Simpson RM AD - Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland. FAU - Dubois, Wendy AU - Dubois W AD - Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland. FAU - Testa, Joseph R AU - Testa JR AUID- ORCID: 0000-0003-1301-5175 AD - Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania. mockb@mail.nih.gov joseph.testa@fccc.edu. FAU - Mock, Beverly A AU - Mock BA AUID- ORCID: 0000-0003-2479-4549 AD - Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland. mockb@mail.nih.gov joseph.testa@fccc.edu. LA - eng GR - ZIA BC011064/ImNIH/Intramural NIH HHS/United States GR - Z01 BC010008/ImNIH/Intramural NIH HHS/United States GR - R01 CA077429/CA/NCI NIH HHS/United States GR - ZIA BC010008/ImNIH/Intramural NIH HHS/United States GR - ZIA BC011065/ImNIH/Intramural NIH HHS/United States GR - P30 CA006927/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural DEP - 20200803 PL - United States TA - Mol Cancer Ther JT - Molecular cancer therapeutics JID - 101132535 RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.22 (CDK6 protein, human) RN - EC 2.7.11.22 (Cyclin-Dependent Kinase 6) SB - IM MH - Animals MH - Carcinogenesis MH - Cyclin-Dependent Kinase 6/*metabolism MH - Down-Regulation MH - Gene Expression Profiling/*methods MH - Mice MH - Mice, Transgenic MH - TOR Serine-Threonine Kinases/*metabolism PMC - PMC9574474 MID - NIHMS1613877 COIS- Competing interests The authors declare no competing interests. Conflict of Interest: The authors declare no potential conflicts of interest. EDAT- 2020/08/05 06:00 MHDA- 2021/08/07 06:00 PMCR- 2022/10/17 CRDT- 2020/08/05 06:00 PHST- 2019/07/05 00:00 [received] PHST- 2020/01/14 00:00 [revised] PHST- 2020/07/13 00:00 [accepted] PHST- 2020/08/05 06:00 [pubmed] PHST- 2021/08/07 06:00 [medline] PHST- 2020/08/05 06:00 [entrez] PHST- 2022/10/17 00:00 [pmc-release] AID - 1535-7163.MCT-19-0671 [pii] AID - 10.1158/1535-7163.MCT-19-0671 [doi] PST - ppublish SO - Mol Cancer Ther. 2020 Oct;19(10):2221-2232. doi: 10.1158/1535-7163.MCT-19-0671. Epub 2020 Aug 3.