Pan-Raf co-operates with PI3K-dependent signalling and critically contributes to myeloma cell survival independently of mutated RAS.
Direct therapeutic targeting of oncogenic RAS is currently still impossible due to lack of suitable pharmacological inhibitors. Because specific blockade of druggable RAS effectors might represent an alternative treatment approach, we evaluated the role of the Raf complex for multiple myeloma (MM) pathobiology. We found frequent overexpression of the Raf isoforms (A-, B- and C-Raf) and downstream activation of MEK1,2/ERK1,2 in MM cells. Concomitant inhibition of all Raf isoforms (pan-Raf inhibition) by RNAi or pharmacological inhibitors was required to strongly induce apoptosis in human MM cell lines (HMCLs), in primary MM cells in vitro, and in a syngeneic MM mouse model in vivo. The anti-MM effect of pan-Raf inhibition did not correlate with the RAS mutation status, and functionally appeared to involve both MEK-dependent and -independent mechanisms. Furthermore, transcriptome analyses revealed that pan-Raf activity affects PI3K-dependent signalling, thus highlighting a functional link between the RAS/Raf and PI3K/mTOR/Akt pro-survival pathways. Accordingly, pharmacological inhibition of PI3K strongly enhanced the anti-MM effect of pan-Raf inhibition in MM cell lines and in primary MM cells in vitro and in vivo. Concomitant pan-Raf/PI3K inhibition was also effective in carfilzomib- and lenalidomide-resistant MM models underscoring that this attractive therapeutic anti-MM strategy is suitable for immediate clinical translation.
Department of Internal Medicine II, Translational Oncology, University Hospital of Würzburg, Würzburg, Germany.
E
E
Müller
Department of Internal Medicine II, Translational Oncology, University Hospital of Würzburg, Würzburg, Germany.
S
S
Bauer
Department of Internal Medicine II, Translational Oncology, University Hospital of Würzburg, Würzburg, Germany.
T
T
Stühmer
Institute of Pathology and Comprehensive Cancer Center Mainfranken (CCCMF), University of Würzburg, Würzburg, Germany.
A
A
Mottok
Core Unit Systems Medicine, Interdisciplinary Clinical Research Center, University of Würzburg, Würzburg, Germany.
C-J
CJ
Scholz
Department of Internal Medicine II, Translational Oncology, University Hospital of Würzburg, Würzburg, Germany.
T
T
Steinbrunn
Department of Internal Medicine II, Translational Oncology, University Hospital of Würzburg, Würzburg, Germany.
D
D
Brünnert
Department of Internal Medicine II, Translational Oncology, University Hospital of Würzburg, Würzburg, Germany.
A
A
Brandl
Department of Internal Medicine II, Translational Oncology, University Hospital of Würzburg, Würzburg, Germany.
H
H
Schraud
Department of Internal Medicine II, Translational Oncology, University Hospital of Würzburg, Würzburg, Germany.
S
S
Kreßmann
Department of Internal Medicine II, Translational Oncology, University Hospital of Würzburg, Würzburg, Germany.
A
A
Beilhack
Institute of Pathology and Comprehensive Cancer Center Mainfranken (CCCMF), University of Würzburg, Würzburg, Germany.
A
A
Rosenwald
Comprehensive Cancer Center Mainfranken (CCCMF), University Hospital of Würzburg, Würzburg, Germany.
R C
RC
Bargou
Department of Internal Medicine II, Translational Oncology, University Hospital of Würzburg, Würzburg, Germany.
M
M
Chatterjee
D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D007527:Isoenzymes; D000077269:Lenalidomide; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology; D018631:ras Proteins / Q000235:genetics*
D007527:Isoenzymes; D000077269:Lenalidomide; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; D013792:Thalidomide; D018631:ras Proteins
Clin Lymphoma Myeloma Leuk. 2014 Oct;14 (5):e161-3
24997557
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
16199517
Mol Biosyst. 2013 Apr 5;9(4):551-8
23212737
PLoS One. 2013 Jul 03;8(7):e67583
23844038
Cancer Discov. 2013 Aug;3(8):862-9
23612012
Nat Rev Cancer. 2012 Apr 12;12(5):335-48
22495321
Blood. 2008 Oct 15;112(8):3403-11
18635812
PLoS One. 2014 Jun 05;9(6):e97443
24901949
Oncogene. 2001 Jun 14;20(27):3553-62
11429702
Oncotarget. 2015 Sep 15;6(27):24205-17
26090869
Cancer Cell. 2015 Sep 14;28(3):384-98
26343583
Nature. 2011 Mar 24;471(7339):467-72
21430775
J Clin Oncol. 2005 Sep 20;23(27):6771-90
16170185
Blood. 2002 Nov 1;100(9):3311-8
12384432
Bioorg Med Chem Lett. 2012 Jan 15;22(2):789-92
22222036
Cancer Cell. 2015 Sep 14;28(3):279-81
26373275
Cancer Cell. 2014 Jan 13;25(1):91-101
24434212
Cancer Res. 2006 Dec 1;66(23):11100-5
17145850
PLoS One. 2012;7(12):e52398
23300660
Br J Haematol. 2004 Mar;124(5):595-603
14871245
Immunol Res. 2011 Apr;49(1-3):248-68
21170740
Nat Rev Drug Discov. 2014 Dec;13(12):928-42
25435214
Br J Haematol. 2014 Aug;166(4):529-39
24766330
Expert Opin Drug Metab Toxicol. 2013 Jul;9(7):893-9
23621583
Br J Haematol. 2010 May;149(4):529-36
20331455
Science. 2002 Apr 19;296(5567):550-3
11910072
Blood Cancer J. 2013 Feb 08;3:e102
23396385
J Exp Med. 1989 Nov 1;170(5):1715-25
2681517
Nat Rev Clin Oncol. 2010 May;7(5):251-65
20351699
Br J Haematol. 2012 Nov;159(4):430-40
22985491
Dermatol Ther (Heidelb). 2015 Sep;5(3):151-69
26387031
Mol Cancer. 2015 Feb 03;14 :27
25645078
Bioorg Med Chem Lett. 2006 Jan 15;16(2):378-81
16260133
Mol Cancer Ther. 2015 Dec;14 (12 ):2700-11
26351322
ACS Med Chem Lett. 2013 Feb 07;4(3):358-62
24900673
Blood. 2011 Feb 10;117(6):1998-2004
21149634
Blood. 2014 Oct 2;124(14):2190-5
25075128
Genes Cancer. 2011 Mar;2(3):232-60
21779496
Blood. 2004 Dec 1;104(12):3712-21
15297310
Cancer Res. 2013 Dec 1;73(23):7043-55
24121489