Blocking downstream signaling pathways in the context of HDAC inhibition promotes apoptosis preferentially in cells harboring mutant Ras

被引:12
作者
Bahr, Julian C. [1 ]
Robey, Robert W. [1 ,2 ]
Luchenko, Victoria [1 ]
Basseville, Agnes [1 ]
Chakraborty, Arup R. [1 ]
Kozlowski, Hanna [2 ]
Pauly, Gary T. [3 ]
Patel, Paresma [3 ]
Schneider, Joel P. [3 ]
Gottesman, Michael M. [2 ]
Bates, Susan E. [1 ,4 ]
机构
[1] NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA
[2] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA
[3] NCI, Chem Biol Lab, Frederick Canc Res Ctr, Frederick, MD 21702 USA
[4] Columbia Univ, Med Ctr, Div Hematol Oncol, New York, NY 10032 USA
关键词
romidepsin; Ras mutation; apoptosis; MEK inhibitor; AKT inhibitor; HISTONE DEACETYLASE INHIBITOR; PANCREATIC-CANCER CELLS; ADVANCED SOLID TUMORS; BUPARLISIB BKM120; COLORECTAL-CANCER; INDUCE APOPTOSIS; DOSE-ESCALATION; MEK INHIBITORS; WHOLE-EXOME; MOUSE MODEL;
D O I
10.18632/oncotarget.12001
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
We previously demonstrated activation of the mitogen-activated protein kinase (MAPK) pathway in a series of romidepsin-selected T-cell lymphoma cell lines as a mechanism of resistance to the histone deacetylase inhibitor (HDI), romidepsin. As Ras mutation leads to activation of both the MAPK and the phosphoinositide 3-kinase (PI3K) pathway, we examined whether combining romidepsin with small molecule pathway inhibitors would lead to increased apoptosis in cancers harboring Ras mutations. We treated 18 Ras mutant or wild-type cell lines with romidepsin in the presence of a MEK inhibitor (PD-0325901) and/or an AKT inhibitor (MK-2206) and examined apoptosis by flow cytometry. A short-term treatment schedule of romidepsin (25 ng/ml for 6 h) was used to more closely model clinical administration. Romidepsin in combination with a MEK and an AKT inhibitor induced apoptosis preferentially in cells harboring mutant versus wild-type Ras (69.1% vs. 21.1%, p < 0.0001). Similar results were found in a subset of cell lines when belinostat was combined with the MEK and AKT inhibitors and when romidepsin was combined with the dual extracellular signaling-related kinase (ERK)/PI3K inhibitor, D-87503, which inhibited both the MAPK and PI3K pathways at 5-10 mu M. The observed apoptosis was caspase-dependent and required Bak and Bax expression. Cells with wild-type or mutant Ras treated with romidepsin alone or in combination with the MEK inhibitor displayed increased expression of proapoptotic Bim. We thus conclude that cancers bearing Ras mutations, such as pancreatic cancer, can be targeted by the combination of an HDI and a dual inhibitor of the MAPK and PI3K pathways.
引用
收藏
页码:69804 / 69815
页数:12
相关论文
共 45 条
[1]   Combined MEK and PI3K Inhibition in a Mouse Model of Pancreatic Cancer [J].
Alagesan, Brinda ;
Contino, Gianmarco ;
Guimaraes, Alexander R. ;
Corcoran, Ryan B. ;
Deshpande, Vikram ;
Wojtkiewicz, Gregory R. ;
Hezel, Aram F. ;
Wong, Kwok-Kin ;
Loda, Massimo ;
Weissleder, Ralph ;
Benes, Cyril ;
Engelman, Jeffrey A. ;
Bardeesy, Nabeel .
CLINICAL CANCER RESEARCH, 2015, 21 (02) :396-404
[2]   Substitutions of potentially phosphorylatable serine residues of Bax reveal how they may regulate its interaction with mitochondria [J].
Arokium, Hubert ;
Ouerfelli, Hakim ;
Velours, Gisele ;
Camougrand, Nadine ;
Vallette, Francois M. ;
Manon, Stephen .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (48) :35104-35112
[3]   A Phase Ib Dose-Escalation Study of the Oral Pan-PI3K Inhibitor Buparlisib (BKM120) in Combination with the Oral MEK1/2 Inhibitor Trametinib (GSK1120212) in Patients with Selected Advanced Solid Tumors [J].
Bedard, Philippe L. ;
Tabernero, Josep ;
Janku, Filip ;
Wainberg, Zev A. ;
Paz-Ares, Luis ;
Vansteenkiste, Johan ;
Van Cutsem, Eric ;
Perez-Garcia, Jose ;
Stathis, Anastasios ;
Britten, Carolyn D. ;
Le, Ngocdiep ;
Carter, Kirsten ;
Demanse, David ;
Csonka, Denes ;
Peters, Malte ;
Zubel, Angela ;
Nauwelaerts, Heidi ;
Sessa, Cristiana .
CLINICAL CANCER RESEARCH, 2015, 21 (04) :730-738
[4]   HDAC inhibitors induce tumor-cell-selective pro-apoptotic transcriptional responses [J].
Bolden, J. E. ;
Shi, W. ;
Jankowski, K. ;
Kan, C-Y ;
Cluse, L. ;
Martin, B. P. ;
MacKenzie, K. L. ;
Smyth, G. K. ;
Johnstone, R. W. .
CELL DEATH & DISEASE, 2013, 4 :e519-e519
[5]   Histone deacetylase inhibitor (HDACI) mechanisms of action: Emerging insights [J].
Bose, Prithviraj ;
Dai, Yun ;
Grant, Steven .
PHARMACOLOGY & THERAPEUTICS, 2014, 143 (03) :323-336
[6]   MAPK pathway activation leads to Bim loss and histone deacetylase inhibitor resistance: rationale to combine romidepsin with an MEK inhibitor [J].
Chakraborty, Arup R. ;
Robey, Robert W. ;
Luchenko, Victoria L. ;
Zhan, Zhirong ;
Piekarz, Richard L. ;
Gillet, Jean-Pierre ;
Kossenkov, Andrew V. ;
Wilkerson, Julia ;
Showe, Louise C. ;
Gottesman, Michael M. ;
Collie, Nathan L. ;
Bates, Susan E. .
BLOOD, 2013, 121 (20) :4115-4125
[7]   Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophils [J].
Gardai, SJ ;
Hildeman, DA ;
Frankel, SK ;
Whitlock, BB ;
Frasch, SC ;
Borregaard, N ;
Marrack, P ;
Bratton, DL ;
Henson, PM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (20) :21085-21095
[8]  
Hanker Ariella B, 2009, J Mol Signal, V4, P5, DOI 10.1186/1750-2187-4-5
[9]   Survival factor-induced extracellular signal-regulated kinase phosphorylates BIM, inhibiting its association with BAX and proapoptotic activity [J].
Harada, H ;
Quearry, B ;
Ruiz-Vela, A ;
Korsmeyer, SJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (43) :15313-15317
[10]   Failure to Induce Apoptosis via BCL-2 Family Proteins Underlies Lack of Efficacy of Combined MEK and PI3K Inhibitors for KRAS-Mutant Lung Cancers [J].
Hata, Aaron N. ;
Yeo, Alan ;
Faber, Anthony C. ;
Lifshits, Eugene ;
Chen, Zhao ;
Cheng, Katherine A. ;
Walton, Zandra ;
Sarosiek, Kristopher A. ;
Letai, Anthony ;
Heist, Rebecca S. ;
Mino-Kenudson, Mari ;
Wong, Kwok-Kin ;
Engelman, Jeffrey A. .
CANCER RESEARCH, 2014, 74 (11) :3146-3156