XPO1-dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer.
The common participation of oncogenic KRAS proteins in many of the most lethal human cancers, together with the ease of detecting somatic KRAS mutant alleles in patient samples, has spurred persistent and intensive efforts to develop drugs that inhibit KRAS activity. However, advances have been hindered by the pervasive inter- and intra-lineage diversity in the targetable mechanisms that underlie KRAS-driven cancers, limited pharmacological accessibility of many candidate synthetic-lethal interactions and the swift emergence of unanticipated resistance mechanisms to otherwise effective targeted therapies. Here we demonstrate the acute and specific cell-autonomous addiction of KRAS-mutant non-small-cell lung cancer cells to receptor-dependent nuclear export. A multi-genomic, data-driven approach, utilizing 106 human non-small-cell lung cancer cell lines, was used to interrogate 4,725 biological processes with 39,760 short interfering RNA pools for those selectively required for the survival of KRAS-mutant cells that harbour a broad spectrum of phenotypic variation. Nuclear transport machinery was the sole process-level discriminator of statistical significance. Chemical perturbation of the nuclear export receptor XPO1 (also known as CRM1), with a clinically available drug, revealed a robust synthetic-lethal interaction with native or engineered oncogenic KRAS both in vitro and in vivo. The primary mechanism underpinning XPO1 inhibitor sensitivity was intolerance to the accumulation of nuclear IκBα (also known as NFKBIA), with consequent inhibition of NFκB transcription factor activity. Intrinsic resistance associated with concurrent FSTL5 mutations was detected and determined to be a consequence of YAP1 activation via a previously unappreciated FSTL5-Hippo pathway regulatory axis. This occurs in approximately 17% of KRAS-mutant lung cancers, and can be overcome with the co-administration of a YAP1-TEAD inhibitor. These findings indicate that clinically available XPO1 inhibitors are a promising therapeutic strategy for a considerable cohort of patients with lung cancer when coupled to genomics-guided patient selection and observation.
Department of Cell Biology, UTSW Medical Center, Dallas, Texas 75390, USA.
Jimi
J
Kim
Department of Cell Biology, UTSW Medical Center, Dallas, Texas 75390, USA.
Elizabeth
E
McMillan
Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 120-752, South Korea.
Hyun Seok
HS
Kim
Internal Medicine, UTSW Medical Center, Dallas, Texas 75390, USA.
Niranjan
N
Venkateswaran
Department of Cell Biology, UTSW Medical Center, Dallas, Texas 75390, USA.
Gurbani
G
Makkar
Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
Jaime
J
Rodriguez-Canales
Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
Pamela
P
Villalobos
KU Leuven Department of Microbiology and Immunology, 3000 Leuven, Belgium.
Jasper Edgar
JE
Neggers
Department of Cell Biology, UTSW Medical Center, Dallas, Texas 75390, USA.
Saurabh
S
Mendiratta
Biochemistry, UTSW Medical Center, Dallas, Texas 75390, USA.
Shuguang
S
Wei
Karyopharm Therapeutics, Newton, Massachusetts 02459, USA.
Yosef
Y
Landesman
Karyopharm Therapeutics, Newton, Massachusetts 02459, USA.
William
W
Senapedis
Karyopharm Therapeutics, Newton, Massachusetts 02459, USA.
Erkan
E
Baloglu
Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
Chi-Wan B
CB
Chow
Hamon Center, UTSW Medical Center, Dallas, Texas 75390, USA.
Robin E
RE
Frink
Hamon Center, UTSW Medical Center, Dallas, Texas 75390, USA.
Boning
B
Gao
Biochemistry, UTSW Medical Center, Dallas, Texas 75390, USA.
Michael
M
Roth
Hamon Center, UTSW Medical Center, Dallas, Texas 75390, USA.
John D
JD
Minna
KU Leuven Department of Microbiology and Immunology, 3000 Leuven, Belgium.
Dirk
D
Daelemans
Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
Ignacio I
II
Wistuba
Biochemistry, UTSW Medical Center, Dallas, Texas 75390, USA.
Bruce A
BA
Posner
Internal Medicine, UTSW Medical Center, Dallas, Texas 75390, USA.
Pier Paolo
PP
Scaglioni
Department of Cell Biology, UTSW Medical Center, Dallas, Texas 75390, USA.
Michael A
MA
White
D021581:Active Transport, Cell Nucleus / Q000187:drug effects*; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D038702:Follistatin-Related Proteins / Q000235:genetics; D005804:Genes, Lethal / Q000235:genetics; D000090683:Hippo Signaling Pathway; D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011166:Porphyrins / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077362:Verteporfin; D023041:Xenograft Model Antitumor Assays; D000091102:YAP-Signaling Proteins; D000097606:Exportin 1 Protein
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D038702:Follistatin-Related Proteins; D028884:Karyopherins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011166:Porphyrins; D017346:Protein Serine-Threonine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors; D000077362:Verteporfin; D000091102:YAP-Signaling Proteins; D000097606:Exportin 1 Protein; C569961:FSTL5 protein, human; C117307:KRAS protein, human; C057182:TEAD1 protein, human; C088374:YAP1 protein, human
Clin Cancer Res. 2009 Aug 1;15(15):4829-37
19622585
J Biol Chem. 2003 Jan 17;278(3):1450-6
12403772
Cell. 2012 Apr 27;149(3):642-55
22541434
Nat Rev Drug Discov. 2014 Nov;13(11):828-51
25323927
Cancer Res. 2008 Sep 1;68(17):6913-21
18757405
Blood. 2012 Nov 29;120(23):4621-34
23034282
Genomics Inform. 2013 Mar;11(1):55-7
23613684
RNA. 2006 Jul;12(7):1179-87
16682560
Chem Biol. 2015 Jan 22;22(1):107-16
25579209
Cell. 2013 Oct 24;155(3):552-66
24243015
J Clin Oncol. 2016 Dec;34(34):4142-4150
26926685
Cell. 2015 Nov 5;163(4):811-28
26544935
Genome Res. 2003 Nov;13(11):2498-504
14597658
J Assist Reprod Genet. 2011 Sep;28(10):939-50
21822582
Br J Haematol. 2013 Apr;161(1):117-27
23373539
Genes Cancer. 2014 Apr;5(1-2):41-55
24955217
Science. 2007 Feb 16;315(5814):972-6
17218491
Nature. 2009 Nov 5;462(7269):108-12
19847166
Nat Genet. 2015 Mar;47(3):250-6
25665005
Cancer Res. 2005 Mar 1;65(5):1642-6
15753357
Cell. 2009 May 29;137(5):835-48
19490893
Nat Cell Biol. 2015 Apr;17(4):500-10
25751140
Genome Biol. 2009;10(3):R25
19261174
J Natl Cancer Inst. 2005 Mar 2;97(5):339-46
15741570
Cell Rep. 2015 Mar 10;:null
25772357
Immunity. 2011 Feb 25;34(2):188-200
21333553
Cell. 2009 May 29;137(5):821-34
19490892
Nature. 2007 Apr 12;446(7137):815-9
17429401
J Cell Biochem Suppl. 1996;24:32-91
8806092
Cell. 2014 Jul 3;158(1):171-84
24954536
Nat Protoc. 2009;4(7):1064-72
19561589
Mol Cancer Ther. 2014 Mar;13(3):675-86
24431073
Nature. 2009 Nov 5;462(7269):104-7
19847165
Cell. 2008 Nov 28;135(5):852-64
19012953
Cell. 2014 Jul 3;158(1):185-97
24954535