Adaptive translational reprogramming of metabolism limits the response to targeted therapy in BRAF
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
01 03 2022
01 03 2022
Historique:
received:
07
10
2019
accepted:
07
02
2022
entrez:
2
3
2022
pubmed:
3
3
2022
medline:
13
4
2022
Statut:
epublish
Résumé
Despite the success of therapies targeting oncogenes in cancer, clinical outcomes are limited by residual disease that ultimately results in relapse. This residual disease is often characterized by non-genetic adaptive resistance, that in melanoma is characterised by altered metabolism. Here, we examine how targeted therapy reprograms metabolism in BRAF-mutant melanoma cells using a genome-wide RNA interference (RNAi) screen and global gene expression profiling. Using this systematic approach we demonstrate post-transcriptional regulation of metabolism following BRAF inhibition, involving selective mRNA transport and translation. As proof of concept we demonstrate the RNA processing kinase U2AF homology motif kinase 1 (UHMK1) associates with mRNAs encoding metabolism proteins and selectively controls their transport and translation during adaptation to BRAF-targeted therapy. UHMK1 inactivation induces cell death by disrupting therapy induced metabolic reprogramming, and importantly, delays resistance to BRAF and MEK combination therapy in multiple in vivo models. We propose selective mRNA processing and translation by UHMK1 constitutes a mechanism of non-genetic resistance to targeted therapy in melanoma by controlling metabolic plasticity induced by therapy.
Identifiants
pubmed: 35232962
doi: 10.1038/s41467-022-28705-x
pii: 10.1038/s41467-022-28705-x
pmc: PMC8888590
doi:
Substances chimiques
Protein Kinase Inhibitors
0
RNA, Messenger
0
BRAF protein, human
EC 2.7.11.1
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1100Informations de copyright
© 2022. Crown.
Références
Robert, C. et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N. Engl. J. Med. 372, 30–39 (2015).
pubmed: 25399551
doi: 10.1056/NEJMoa1412690
Larkin, J. et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N. Engl. J. Med. 371, 1867–1876 (2014).
pubmed: 25265494
doi: 10.1056/NEJMoa1408868
Lim, S. Y., Menzies, A. M. & Rizos, H. Mechanisms and strategies to overcome resistance to molecularly targeted therapy for melanoma. Cancer 123, 2118–2129 (2017).
pubmed: 28543695
doi: 10.1002/cncr.30435
Menon, D. R. et al. A stress-induced early innate response causes multidrug tolerance in melanoma. Oncogene 34, 4545 (2015).
pubmed: 25619837
doi: 10.1038/onc.2014.432
Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010).
pubmed: 20371346
pmcid: 2851638
doi: 10.1016/j.cell.2010.02.027
Su, Y. et al. Single-cell analysis resolves the cell state transition and signaling dynamics associated with melanoma drug-induced resistance. Proc. Natl Acad. Sci. USA 114, 13679–13684 (2017).
pubmed: 29229836
pmcid: 5748184
doi: 10.1073/pnas.1712064115
Rambow, F. et al. Toward minimal residual disease-directed therapy in melanoma. Cell 174, 843–855.e819 (2018).
pubmed: 30017245
doi: 10.1016/j.cell.2018.06.025
Marine, J. C., Dawson, S. J. & Dawson, M. A. Non-genetic mechanisms of therapeutic resistance in cancer. Nat. Rev. Cancer 20, 743–756 (2020).
pubmed: 33033407
doi: 10.1038/s41568-020-00302-4
Marin-Bejar, O. et al. Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma. Cancer Cell 39, 1135–1149.e8 (2021).
Parmenter, T. J. et al. Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis. Cancer Discov. 4, 423–433 (2014).
pubmed: 24469106
pmcid: 4110245
doi: 10.1158/2159-8290.CD-13-0440
McArthur, G. A. et al. Marked, homogeneous, and early [18F]fluorodeoxyglucose-positron emission tomography responses to vemurafenib in BRAF-mutant advanced melanoma. J. Clin. Oncol. 30, 1628–1634 (2012).
pubmed: 22454415
pmcid: 5950495
doi: 10.1200/JCO.2011.39.1938
Haq, R. et al. Oncogenic BRAF regulates oxidative metabolism via PGC1alpha and MITF. Cancer Cell 23, 302–315 (2013).
pubmed: 23477830
pmcid: 3635826
doi: 10.1016/j.ccr.2013.02.003
Gopal, Y. N. et al. Inhibition of mTORC1/2 overcomes resistance to MAPK pathway inhibitors mediated by PGC1alpha and oxidative phosphorylation in melanoma. Cancer Res. 74, 7037–7047 (2014).
pubmed: 25297634
pmcid: 4347853
doi: 10.1158/0008-5472.CAN-14-1392
Zhang, G. et al. Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors. J. Clin. Investig. 126, 1834–1856 (2016).
pubmed: 27043285
pmcid: 4855947
doi: 10.1172/JCI82661
Kordes, S. et al. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 16, 839–847 (2015).
pubmed: 26067687
doi: 10.1016/S1470-2045(15)00027-3
Hulea, L. et al. Translational and HIF-1alpha-dependent metabolic reprogramming underpin metabolic plasticity and responses to kinase inhibitors and biguanides. Cell Metab. 28, 817–832.e818 (2018).
pubmed: 30244971
pmcid: 7252493
doi: 10.1016/j.cmet.2018.09.001
Smith, L. K. et al. Genome-wide RNAi screen for genes regulating glycolytic response to vemurafenib in BRAF(V600) melanoma cells. Sci. Data 7, 339 (2020).
pubmed: 33046726
pmcid: 7550327
doi: 10.1038/s41597-020-00683-z
Smith, L. K. et al. Genome-wide RNAi screen for genes regulating glycolytic response to vemurafenib in BRAFV600 melanoma cells. PubChem Bioassay https://pubchem.ncbi.nlm.nih.gov/bioassay/1508588 (2020).
Kardos, G. R., Dai, M. S. & Robertson, G. P. Growth inhibitory effects of large subunit ribosomal proteins in melanoma. Pigment Cell Melanoma Res. 27, 801–812 (2014).
pubmed: 24807543
pmcid: 4416652
doi: 10.1111/pcmr.12259
Boussemart, L. et al. eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies. Nature 513, 105–109 (2014).
pubmed: 25079330
doi: 10.1038/nature13572
Feng, Y. et al. SBI-0640756 attenuates the growth of clinically unresponsive melanomas by disrupting the eIF4F translation initiation complex. Cancer Res. 75, 5211–5218 (2015).
pubmed: 26603897
pmcid: 4681635
doi: 10.1158/0008-5472.CAN-15-0885
Johannessen, C. M. et al. A melanocyte lineage program confers resistance to MAP kinase pathway inhibition. Nature 504, 138–142 (2013).
pubmed: 24185007
pmcid: 4098832
doi: 10.1038/nature12688
El-Naggar, A. M. & Sorensen, P. H. Translational control of aberrant stress responses as a hallmark of cancer. J. Pathol. 244, 650–666 (2018).
pubmed: 29293271
doi: 10.1002/path.5030
Hugo, W. et al. Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. Cell 162, 1271–1285 (2015).
pubmed: 26359985
pmcid: 4821508
doi: 10.1016/j.cell.2015.07.061
Gandin, V. et al. Polysome fractionation and analysis of mammalian translatomes on a genome-wide scale. J. Vis. Exp. 51455 (2014).
Warner, J. R., Knopf, P. M. & Rich, A. A multiple ribosomal structure in protein synthesis. Proc. Natl Acad. Sci. USA 49, 122–129 (1963).
pubmed: 13998950
pmcid: 300639
doi: 10.1073/pnas.49.1.122
Oertlin, C. et al. Generally applicable transcriptome-wide analysis of translation using anota2seq. Nucleic Acids Res. 47, e70 (2019).
Maucuer, A. et al. KIS is a protein kinase with an RNA recognition motif. J. Biol. Chem. 272, 23151–23156 (1997).
pubmed: 9287318
doi: 10.1074/jbc.272.37.23151
Cambray, S. et al. Protein kinase KIS localizes to RNA granules and enhances local translation. Mol. Cell. Biol. 29, 726–735 (2009).
pubmed: 19015237
doi: 10.1128/MCB.01180-08
Pedraza, N. et al. KIS, a kinase associated with microtubule regulators, enhances translation of AMPA receptors and stimulates dendritic spine remodeling. J. Neurosci. 34, 13988–13997 (2014).
pubmed: 25319695
pmcid: 6705288
doi: 10.1523/JNEUROSCI.1573-14.2014
Boehm, M. et al. A growth factor-dependent nuclear kinase phosphorylates p27(Kip1) and regulates cell cycle progression. EMBO J. 21, 3390–3401 (2002).
pubmed: 12093740
pmcid: 126092
doi: 10.1093/emboj/cdf343
Sullivan, L. B. et al. Supporting aspartate biosynthesis is an essential function of respiration in proliferating. Cells Cell 162, 552–563 (2015).
pubmed: 26232225
doi: 10.1016/j.cell.2015.07.017
Manceau, V., Kielkopf, C. L., Sobel, A. & Maucuer, A. Different requirements of the kinase and UHM domains of KIS for its nuclear localization and binding to splicing factors. J. Mol. Biol. 381, 748–762 (2008).
pubmed: 18588901
pmcid: 2632974
doi: 10.1016/j.jmb.2008.06.026
Kielkopf, C. L., Lücke, S. & Green, M. R. U2AF homology motifs: protein recognition in the RRM world. Genes Dev. 18, 1513–1526 (2004).
pubmed: 15231733
doi: 10.1101/gad.1206204
Maris, C., Dominguez, C. & Allain, F. H. The RNA recognition motif, a plastic RNA-binding platform to regulate post-transcriptional gene expression. FEBS J. 272, 2118–2131 (2005).
pubmed: 15853797
doi: 10.1111/j.1742-4658.2005.04653.x
Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021).
Corsini, L. et al. U2AF-homology motif interactions are required for alternative splicing regulation by SPF45. Nat. Struct. Mol. Biol. 14, 620–629 (2007).
pubmed: 17589525
doi: 10.1038/nsmb1260
Biancur, D. E. et al. Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism. Nat. Commun. 8, 15965 (2017).
pubmed: 28671190
pmcid: 5500878
doi: 10.1038/ncomms15965
Ghosh, J. C. et al. Adaptive mitochondrial reprogramming and resistance to PI3K therapy. J. Natl Cancer Inst. 107, dju502 (2015).
Hernandez-Davies, J. E. et al. Vemurafenib resistance reprograms melanoma cells towards glutamine dependence. J. Transl. Med. 13, 210 (2015).
pubmed: 26139106
pmcid: 4490757
doi: 10.1186/s12967-015-0581-2
Caino, M. C. et al. PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion. Proc. Natl Acad. Sci. USA 112, 8638–8643 (2015).
pubmed: 26124089
pmcid: 4507184
doi: 10.1073/pnas.1500722112
Baenke, F. et al. Resistance to BRAF inhibitors induces glutamine dependency in melanoma cells. Mol. Oncol. 10, 73–84 (2015).
Kluza, J. et al. Inactivation of the HIF-1alpha/PDK3 signaling axis drives melanoma toward mitochondrial oxidative metabolism and potentiates the therapeutic activity of pro-oxidants. Cancer Res. 72, 5035–5047 (2012).
pubmed: 22865452
doi: 10.1158/0008-5472.CAN-12-0979
Rapino, F. et al. Codon-specific translation reprogramming promotes resistance to targeted therapy. Nature 558, 605–609 (2018).
pubmed: 29925953
doi: 10.1038/s41586-018-0243-7
Lamper, A. M., Fleming, R. H., Ladd, K. M. & Lee, A. S. Y. A phosphorylation-regulated eIF3d translation switch mediates cellular adaptation to metabolic stress. Science 370, 853–856 (2020).
pubmed: 33184215
doi: 10.1126/science.abb0993
Falletta, P. et al. Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma. Genes Dev. 31, 18–33 (2017).
pubmed: 28096186
pmcid: 5287109
doi: 10.1101/gad.290940.116
Shen, S. et al. An epitranscriptomic mechanism underlies selective mRNA translation remodelling in melanoma persister cells. Nat. Commun. 10, 5713 (2019).
pubmed: 31844050
pmcid: 6915789
doi: 10.1038/s41467-019-13360-6
Lorent, J. et al. Translational offsetting as a mode of estrogen receptor α-dependent regulation of gene expression. EMBO J. 38, e101323 (2019).
pubmed: 31556460
pmcid: 6885737
doi: 10.15252/embj.2018101323
Bresson, S. et al. Stress-induced translation inhibition through rapid displacement of scanning initiation factors. Mol. cell 80, 470–484.e478 (2020).
pubmed: 33053322
pmcid: 7657445
doi: 10.1016/j.molcel.2020.09.021
Ho, J. J. D. et al. A network of RNA-binding proteins controls translation efficiency to activate anaerobic metabolism. Nat. Commun. 11, 2677 (2020).
pubmed: 32472050
pmcid: 7260222
doi: 10.1038/s41467-020-16504-1
Feng, X. et al. UHMK1 promotes gastric cancer progression through reprogramming nucleotide metabolism. EMBO J. 39, e102541 (2020).
pubmed: 31975428
pmcid: 7049804
Manceau, V., Kremmer, E., Nabel, E. G. & Maucuer, A. The protein kinase KIS impacts gene expression during development and fear conditioning in adult mice. PLoS ONE 7, e43946 (2012).
pubmed: 22937132
pmcid: 3427225
doi: 10.1371/journal.pone.0043946
Wickramasinghe, V. O. & Laskey, R. A. Control of mammalian gene expression by selective mRNA export. Nat. Rev. Mol. Cell Biol. 16, 431–442 (2015).
pubmed: 26081607
doi: 10.1038/nrm4010
Cifdaloz, M. et al. Systems analysis identifies melanoma-enriched pro-oncogenic networks controlled by the RNA binding protein CELF1. Nat. Commun. 8, 2249 (2017).
pubmed: 29269732
pmcid: 5740069
doi: 10.1038/s41467-017-02353-y
Aviner, R. et al. Proteomic analysis of polyribosomes identifies splicing factors as potential regulators of translation during mitosis. Nucleic Acids Res. 45, 5945–5957 (2017).
pubmed: 28460002
pmcid: 5449605
doi: 10.1093/nar/gkx326
Ikediobi, O. N. et al. Mutation analysis of 24 known cancer genes in the NCI-60 cell line set. Mol. Cancer Therapeutics 5, 2606–2612 (2006).
doi: 10.1158/1535-7163.MCT-06-0433
Smith, L. K. et al. Genome-wide RNAi screen for genes regulating glycolytic response to vemurafenib in BRAFV600 melanoma cells - Secondary screen. PubChem Bioassay https://pubchem.ncbi.nlm.nih.gov/bioassay/1508587 (2020).
Barbie, D. A. et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462, 108–112 (2009).
pubmed: 19847166
pmcid: 2783335
doi: 10.1038/nature08460
Hänzelmann, S., Castelo, R. & Guinney, J. GSVA: gene set variation analysis for microarray and RNA-Seq data. BMC Bioinforma. 14, 7 (2013).
doi: 10.1186/1471-2105-14-7
Herranz, N. et al. mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat. Cell Biol. 17, 1205–1217 (2015).
pubmed: 26280535
pmcid: 4589897
doi: 10.1038/ncb3225