ERK5 suppression overcomes FAK inhibitor resistance in mutant KRAS-driven non-small cell lung cancer.
Combination Therapy
Drug Resistance
FAK and ERK5 Inhibitors
Focal Adhesions
Lung Cancer
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: Germany
ID NLM: 101487380
Informations de publication
Date de publication:
13 Sep 2024
13 Sep 2024
Historique:
received:
02
11
2023
accepted:
29
08
2024
revised:
28
08
2024
medline:
14
9
2024
pubmed:
14
9
2024
entrez:
13
9
2024
Statut:
aheadofprint
Résumé
Mutated KRAS serves as the oncogenic driver in 30% of non-small cell lung cancers (NSCLCs) and is associated with metastatic and therapy-resistant tumors. Focal Adhesion Kinase (FAK) acts as a mediator in sustaining KRAS-driven lung tumors, and although FAK inhibitors are currently undergoing clinical development, clinical data indicated that their efficacy in producing long-term anti-tumor responses is limited. Here we revealed two FAK interactors, extracellular-signal-regulated kinase 5 (ERK5) and cyclin-dependent kinase 5 (CDK5), as key players underlying FAK-mediated maintenance of KRAS mutant NSCLC. Inhibition of ERK5 and CDK5 synergistically suppressed FAK function, decreased proliferation and induced apoptosis owing to exacerbated ROS-induced DNA damage. Accordingly, concomitant pharmacological inhibition of ERK5 and CDK5 in a mouse model of Kras
Identifiants
pubmed: 39271958
doi: 10.1038/s44321-024-00138-7
pii: 10.1038/s44321-024-00138-7
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (SNF)
ID : PP00P3_163929
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (SNF)
ID : PP00P3_194810
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (SNF)
ID : 310030_212418
Informations de copyright
© 2024. The Author(s).
Références
Andrews S (2022) FastQC: a quality control tool for high throughput sequence data. Available online at: http://www.bioinformatics.babraham.ac.uk/projects/fastqc
Awad MM, Liu S, Rybkin II, Arbour KC, Dilly J, Zhu VW, Johnson ML, Heist RS, Patil T, Riely GJ et al (2021) Acquired resistance to KRAS(G12C) inhibition in cancer. New Engl J Med 384:2382–2393
pubmed: 34161704
doi: 10.1056/NEJMoa2105281
Bankhead P, Loughrey MB, Fernandez JA, Dombrowski Y, McArt DG, Dunne PD, McQuaid S, Gray RT, Murray LJ, Coleman HG et al (2017) QuPath: open source software for digital pathology image analysis. Sci Rep 7:16878
pubmed: 29203879
pmcid: 5715110
doi: 10.1038/s41598-017-17204-5
Bianchi M, De Lucchini S, Marin O, Turner DL, Hanks SK, Villa-Moruzzi E (2005) Regulation of FAK Ser-722 phosphorylation and kinase activity by GSK3 and PP1 during cell spreading and migration. Biochem J 391:359–370
pubmed: 15975092
pmcid: 1276935
doi: 10.1042/BJ20050282
Brinkman EK, Chen T, Amendola M, van Steensel B (2014) Easy quantitative assessment of genome editing by sequence trace decomposition. Nucleic Acids Res 42:e168
pubmed: 25300484
pmcid: 4267669
doi: 10.1093/nar/gku936
Carmell N, Rominiyi O, Myers KN, McGarrity-Cottrell C, Vanderlinden A, Lad N, Perroux-David E, El-Khamisy SF, Fernando M, Finegan KG et al (2021) Identification and validation of ERK5 as a DNA damage modulating drug target in glioblastoma. Cancers 13:944
pubmed: 33668183
pmcid: 7956595
doi: 10.3390/cancers13050944
Chou TC (2010) Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 70:440–446
pubmed: 20068163
doi: 10.1158/0008-5472.CAN-09-1947
Cicenas J, Kalyan K, Sorokinas A, Stankunas E, Levy J, Meskinyte I, Stankevicius V, Kaupinis A, Valius M (2015) Roscovitine in cancer and other diseases. Ann Transl Med 3:135
pubmed: 26207228
pmcid: 4486920
Diaz Osterman CJ, Ozmadenci D, Kleinschmidt EG, Taylor KN, Barrie AM, Jiang S, Bean LM, Sulzmaier FJ, Jean C, Tancioni I et al (2019) FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy. eLife 8:e47327
pubmed: 31478830
pmcid: 6721800
doi: 10.7554/eLife.47327
DuPage M, Dooley AL, Jacks T (2009) Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase. Nat Protoc 4:1064–1072
pubmed: 19561589
pmcid: 2757265
doi: 10.1038/nprot.2009.95
Edgar R, Domrachev M, Lash AE (2002) Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res 30:207–210
pubmed: 11752295
pmcid: 99122
doi: 10.1093/nar/30.1.207
Espinosa-Gil S, Ivanova S, Alari-Pahissa E, Denizli M, Villafranca-Magdalena B, Vinas-Casas M, Bolinaga-Ayala I, Gamez-Garcia A, Faundez-Vidiella C, Colas E et al (2023) MAP kinase ERK5 modulates cancer cell sensitivity to extrinsic apoptosis induced by death-receptor agonists. Cell Death Dis 14:715
pubmed: 37919293
pmcid: 10622508
doi: 10.1038/s41419-023-06229-6
Gerber DE, Camidge DR, Morgensztern D, Cetnar J, Kelly RJ, Ramalingam SS, Spigel DR, Jeong W, Scaglioni PP, Zhang S et al (2020) Phase 2 study of the focal adhesion kinase inhibitor defactinib (VS-6063) in previously treated advanced KRAS mutant non-small cell lung cancer. Lung Cancer 139:60–67
pubmed: 31739184
doi: 10.1016/j.lungcan.2019.10.033
Giurisato E, Xu Q, Lonardi S, Telfer B, Russo I, Pearson A, Finegan KG, Wang W, Wang J, Gray NS et al (2018) Myeloid ERK5 deficiency suppresses tumor growth by blocking protumor macrophage polarization via STAT3 inhibition. Proc Natl Acad Sci USA 115:E2801–E2810
pubmed: 29507229
pmcid: 5866536
doi: 10.1073/pnas.1707929115
Han H, Cho JW, Lee S, Yun A, Kim H, Bae D, Yang S, Kim CY, Lee M, Kim E et al (2018) TRRUST v2: an expanded reference database of human and mouse transcriptional regulatory interactions. Nucleic Acids Res 46:D380–D386
pubmed: 29087512
doi: 10.1093/nar/gkx1013
Hwang J, Namgung U (2021) Phosphorylation of STAT3 by axonal Cdk5 promotes axonal regeneration by modulating mitochondrial activity. Exp Neurol 335:113511
pubmed: 33098871
doi: 10.1016/j.expneurol.2020.113511
Jackson EL, Willis N, Mercer K, Bronson RT, Crowley D, Montoya R, Jacks T, Tuveson DA (2001) Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev 15:3243–3248
pubmed: 11751630
pmcid: 312845
doi: 10.1101/gad.943001
Jiang H, Liu X, Knolhoff BL, Hegde S, Lee KB, Jiang H, Fields RC, Pachter JA, Lim KH, DeNardo DG (2020a) Development of resistance to FAK inhibition in pancreatic cancer is linked to stromal depletion. Gut 69:122–132
pubmed: 31076405
doi: 10.1136/gutjnl-2018-317424
Jiang W, Cai F, Xu H, Lu Y, Chen J, Liu J, Cao N, Zhang X, Chen X, Huang Q et al (2020b) Extracellular signal regulated kinase 5 promotes cell migration, invasion and lung metastasis in a FAK-dependent manner. Protein Cell 11:825–845
pubmed: 32144580
pmcid: 7647985
doi: 10.1007/s13238-020-00701-1
Jiang W, Jin G, Cai F, Chen X, Cao N, Zhang X, Liu J, Chen F, Wang F, Dong W et al (2019) Extracellular signal-regulated kinase 5 increases radioresistance of lung cancer cells by enhancing the DNA damage response. Exp Mol Med 51:1–20
pubmed: 31757938
pmcid: 6389946
doi: 10.1038/s12276-019-0209-3
Juan CA, Perez de la Lastra JM, Plou FJ, Perez-Lebena E (2021) The chemistry of reactive oxygen species (ROS) revisited: outlining their role in biological macromolecules (DNA, lipids and proteins) and induced pathologies. Int J Mol Sci 22:4642
pubmed: 33924958
pmcid: 8125527
doi: 10.3390/ijms22094642
Kanehisa M, Sato Y, Kawashima M (2022) KEGG mapping tools for uncovering hidden features in biological data. Protein Sci 31:47–53
pubmed: 34423492
doi: 10.1002/pro.4172
Kim D, Langmead B, Salzberg SL (2015) HISAT: a fast spliced aligner with low memory requirements. Nat Methods 12:357–360
pubmed: 25751142
pmcid: 4655817
doi: 10.1038/nmeth.3317
Konstantinidou G, Ramadori G, Torti F, Kangasniemi K, Ramirez RE, Cai Y, Behrens C, Dellinger MT, Brekken RA, Wistuba II et al (2013) RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas. Cancer Discov 3:444–457
pubmed: 23358651
pmcid: 3625467
doi: 10.1158/2159-8290.CD-12-0388
Lanman BA, Allen JR, Allen JG, Amegadzie AK, Ashton KS, Booker SK, Chen JJ, Chen N, Frohn MJ, Goodman G et al (2020) Discovery of a covalent inhibitor of KRAS(G12C) (AMG 510) for the treatment of solid tumors. J Med Chem 63:52–65
pubmed: 31820981
doi: 10.1021/acs.jmedchem.9b01180
Le Tourneau C, Faivre S, Laurence V, Delbaldo C, Vera K, Girre V, Chiao J, Armour S, Frame S, Green SR et al (2010) Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies. Eur J Cancer 46:3243–3250
pubmed: 20822897
doi: 10.1016/j.ejca.2010.08.001
Lee BY, Timpson P, Horvath LG, Daly RJ (2015) FAK signaling in human cancer as a target for therapeutics. Pharmacol Ther 146:132–149
pubmed: 25316657
doi: 10.1016/j.pharmthera.2014.10.001
Lee HJ, Zhuang G, Cao Y, Du P, Kim HJ, Settleman J (2014) Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. Cancer Cell 26:207–221
pubmed: 25065853
doi: 10.1016/j.ccr.2014.05.019
Li MZ, Elledge SJ (2012) SLIC: a method for sequence- and ligation-independent cloning. Methods Mol Biol 852:51–59
pubmed: 22328425
doi: 10.1007/978-1-61779-564-0_5
Liang HL, Hilton G, Mortensen J, Regner K, Johnson CP, Nilakantan V (2009) MnTMPyP, a cell-permeant SOD mimetic, reduces oxidative stress and apoptosis following renal ischemia-reperfusion. Am J Physiol Renal Physiol 296:F266–276
pubmed: 19091787
doi: 10.1152/ajprenal.90533.2008
Liao Y, Smyth GK, Shi W (2014) featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30:923–930
pubmed: 24227677
doi: 10.1093/bioinformatics/btt656
Lietha D, Cai X, Ceccarelli DF, Li Y, Schaller MD, Eck MJ (2007) Structural basis for the autoinhibition of focal adhesion kinase. Cell 129:1177–1187
pubmed: 17574028
pmcid: 2077847
doi: 10.1016/j.cell.2007.05.041
Lim ST, Chen XL, Lim Y, Hanson DA, Vo TT, Howerton K, Larocque N, Fisher SJ, Schlaepfer DD, Ilic D (2008) Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation. Mol Cell 29:9–22
pubmed: 18206965
pmcid: 2234035
doi: 10.1016/j.molcel.2007.11.031
Lochhead PA, Tucker JA, Tatum NJ, Wang J, Oxley D, Kidger AM, Johnson VP, Cassidy MA, Gray NS, Noble MEM et al (2020) Paradoxical activation of the protein kinase-transcription factor ERK5 by ERK5 kinase inhibitors. Nat Commun 11:1383
pubmed: 32170057
pmcid: 7069993
doi: 10.1038/s41467-020-15031-3
Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:550
pubmed: 25516281
pmcid: 4302049
doi: 10.1186/s13059-014-0550-8
Marino S, Vooijs M, van Der Gulden H, Jonkers J, Berns A (2000) Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes Dev 14:994–1004
pubmed: 10783170
pmcid: 316543
doi: 10.1101/gad.14.8.994
Miller DC, Harnor SJ, Martin MP, Noble RA, Wedge SR, Cano C (2023) Modulation of ERK5 activity as a therapeutic anti-cancer strategy. J Med Chem 66:4491–4502
pubmed: 37002872
pmcid: 10108346
doi: 10.1021/acs.jmedchem.3c00072
Mitra SK, Hanson DA, Schlaepfer DD (2005) Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol 6:56–68
pubmed: 15688067
doi: 10.1038/nrm1549
Mohanty A, Nam A, Srivastava S, Jones J, Lomenick B, Singhal SS, Guo L, Cho H, Li A, Behal A et al (2023) Acquired resistance to KRAS G12C small-molecule inhibitors via genetic/nongenetic mechanisms in lung cancer. Sci Adv 9:eade3816
pubmed: 37831779
pmcid: 10575592
doi: 10.1126/sciadv.ade3816
Morgenstern JP, Land H (1990) Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. Nucleic Acids Res 18:3587–3596
pubmed: 2194165
pmcid: 331014
doi: 10.1093/nar/18.12.3587
Ossovskaya V, Lim ST, Ota N, Schlaepfer DD, Ilic D (2008) FAK nuclear export signal sequences. FEBS Lett 582:2402–2406
pubmed: 18549812
pmcid: 2547126
doi: 10.1016/j.febslet.2008.06.004
Pylayeva Y, Gillen KM, Gerald W, Beggs HE, Reichardt LF, Giancotti FG (2009) Ras- and PI3K-dependent breast tumorigenesis in mice and humans requires focal adhesion kinase signaling. J Clin Investig 119:252–266
pubmed: 19147981
pmcid: 2631302
Ramirez RD, Sheridan S, Girard L, Sato M, Kim Y, Pollack J, Peyton M, Zou Y, Kurie JM, Dimaio JM et al (2004) Immortalization of human bronchial epithelial cells in the absence of viral oncoproteins. Cancer Res 64:9027–9034
pubmed: 15604268
doi: 10.1158/0008-5472.CAN-04-3703
Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F (2013) Genome engineering using the CRISPR-Cas9 system. Nat Protoc 8:2281–2308
pubmed: 24157548
pmcid: 3969860
doi: 10.1038/nprot.2013.143
Sanchez-Fdez A, Re-Louhau MF, Rodriguez-Nunez P, Ludena D, Matilla-Almazan S, Pandiella A, Esparis-Ogando A (2021) Clinical, genetic and pharmacological data support targeting the MEK5/ERK5 module in lung cancer. NPJ Precis Oncol 5:78
pubmed: 34404896
pmcid: 8371118
doi: 10.1038/s41698-021-00218-8
Schaller MD, Hildebrand JD, Shannon JD, Fox JW, Vines RR, Parsons JT (1994) Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src. Mol Cell Biol 14:1680–1688
pubmed: 7509446
pmcid: 358526
Schlaepfer DD, Hanks SK, Hunter T, van der Geer P (1994) Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature 372:786–791
pubmed: 7997267
doi: 10.1038/372786a0
Sharma A, Singh K, Almasan A (2012) Histone H2AX phosphorylation: a marker for DNA damage. Methods Mol Biol 920:613–626
pubmed: 22941631
doi: 10.1007/978-1-61779-998-3_40
Siegel RL, Miller KD, Fuchs HE, Jemal A (2021) Cancer statistics, 2021. CA Cancer J Clin 71:7–33
pubmed: 33433946
doi: 10.3322/caac.21654
Skinner HD, Giri U, Yang L, Woo SH, Story MD, Pickering CR, Byers LA, Williams MD, El-Naggar A, Wang J et al (2016) Proteomic profiling identifies PTK2/FAK as a driver of radioresistance in HPV-negative head and neck cancer. Clin Cancer Res 22:4643–4650
pubmed: 27036135
pmcid: 5061056
doi: 10.1158/1078-0432.CCR-15-2785
Srinivas US, Tan BWQ, Vellayappan BA, Jeyasekharan AD (2019) ROS and the DNA damage response in cancer. Redox Biol 25:101084
pubmed: 30612957
doi: 10.1016/j.redox.2018.101084
Stecca B, Rovida E (2019) Impact of ERK5 on the hallmarks of cancer. Int J Mol Sci 20:1426
pubmed: 30901834
pmcid: 6471124
doi: 10.3390/ijms20061426
Stewart SA, Dykxhoorn DM, Palliser D, Mizuno H, Yu EY, An DS, Sabatini DM, Chen IS, Hahn WC, Sharp PA et al (2003) Lentivirus-delivered stable gene silencing by RNAi in primary cells. RNA 9:493–501
pubmed: 12649500
pmcid: 1370415
doi: 10.1261/rna.2192803
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102:15545–15550
pubmed: 16199517
pmcid: 1239896
doi: 10.1073/pnas.0506580102
Sulzmaier FJ, Jean C, Schlaepfer DD (2014) FAK in cancer: mechanistic findings and clinical applications. Nat Rev Cancer 14:598–610
pubmed: 25098269
pmcid: 4365862
doi: 10.1038/nrc3792
Szulc J, Wiznerowicz M, Sauvain MO, Trono D, Aebischer P (2006) A versatile tool for conditional gene expression and knockdown. Nat Methods 3:109–116
pubmed: 16432520
doi: 10.1038/nmeth846
Tang KJ, Constanzo JD, Venkateswaran N, Melegari M, Ilcheva M, Morales JC, Skoulidis F, Heymach JV, Boothman DA, Scaglioni PP (2016) Focal adhesion kinase regulates the DNA damage response and its inhibition radiosensitizes mutant KRAS lung cancer. Clin Cancer Res 22:5851–5863
pubmed: 27220963
pmcid: 5122471
doi: 10.1158/1078-0432.CCR-15-2603
Velazquez ER, Parmar C, Jermoumi M, Mak RH, van Baardwijk A, Fennessy FM, Lewis JH, De Ruysscher D, Kikinis R, Lambin P et al (2013) Volumetric CT-based segmentation of NSCLC using 3D-Slicer. Sci Rep 3:3529
pubmed: 24346241
pmcid: 3866632
doi: 10.1038/srep03529
Villa-Moruzzi E (2007) Targeting of FAK Ser910 by ERK5 and PP1delta in non-stimulated and phorbol ester-stimulated cells. Biochem J 408:7–18
pubmed: 17692050
pmcid: 2049076
doi: 10.1042/BJ20070058
Wang L, Wang S, Li W (2012) RSeQC: quality control of RNA-seq experiments. Bioinformatics 28:2184–2185
pubmed: 22743226
doi: 10.1093/bioinformatics/bts356
Weiner TM, Liu ET, Craven RJ, Cance WG (1993) Expression of focal adhesion kinase gene and invasive cancer. Lancet 342:1024–1025
pubmed: 8105266
doi: 10.1016/0140-6736(93)92881-S
Wiederschain D, Wee S, Chen L, Loo A, Yang G, Huang A, Chen Y, Caponigro G, Yao YM, Lengauer C et al (2009) Single-vector inducible lentiviral RNAi system for oncology target validation. Cell Cycle 8:498–504
pubmed: 19177017
doi: 10.4161/cc.8.3.7701
Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z, Feng T, Zhou L, Tang W, Zhan L et al (2021) clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation 2:100141
pubmed: 34557778
pmcid: 8454663
Xie Z, Sanada K, Samuels BA, Shih H, Tsai LH (2003) Serine 732 phosphorylation of FAK by Cdk5 is important for microtubule organization, nuclear movement, and neuronal migration. Cell 114:469–482
pubmed: 12941275
doi: 10.1016/S0092-8674(03)00605-6
Yang Q, Deng X, Lu B, Cameron M, Fearns C, Patricelli MP, Yates 3rd JR, Gray NS, Lee JD (2010) Pharmacological inhibition of BMK1 suppresses tumor growth through promyelocytic leukemia protein. Cancer Cell 18:258–267
pubmed: 20832753
pmcid: 2939729
doi: 10.1016/j.ccr.2010.08.008
Zhang J, Gao Q, Zhou Y, Dier U, Hempel N, Hochwald SN (2016) Focal adhesion kinase-promoted tumor glucose metabolism is associated with a shift of mitochondrial respiration to glycolysis. Oncogene 35:1926–1942
pubmed: 26119934
doi: 10.1038/onc.2015.256
Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, Benner C, Chanda SK (2019) Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun 10:1523
pubmed: 30944313
pmcid: 6447622
doi: 10.1038/s41467-019-09234-6