Abstract
Combined therapy with anti-BRAF plus anti-MEK is currently used as first-line treatment of patients with metastatic melanomas harboring the somatic BRAF V600E mutation. However, the main issue with targeted therapy is the acquisition of tumor cell resistance. In a majority of resistant melanoma cells, the resistant process consists in epithelial-to-mesenchymal transition (EMT). This process called phenotype switching makes melanoma cells more invasive. Its signature is characterized by MITF low, AXL high, and actin cytoskeleton reorganization through RhoA activation. In parallel of this phenotype switching phase, the resistant cells exhibit an anarchic cell proliferation due to hyper-activation of the MAP kinase pathway. We show that a majority of human melanoma overexpress discoidin domain receptor 2 (DDR2) after treatment. The same result was found in resistant cell lines presenting phenotype switching compared to the corresponding sensitive cell lines. We demonstrate that DDR2 inhibition induces a decrease in AXL expression and reduces stress fiber formation in resistant melanoma cell lines. In this phenotype switching context, we report that DDR2 control cell and tumor proliferation through the MAP kinase pathway in resistant cells in vitro and in vivo. Therefore, inhibition of DDR2 could be a new and promising strategy for countering this resistance mechanism.
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References
Ascierto PA, Kirkwood JM, Grob J-J, Simeone E, Grimaldi AM, Maio M, et al. The role of BRAF V600 mutation in melanoma. J Transl Med. 2012;10:85.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949–54.
Luke JJ, Flaherty KT, Ribas A, Long GV. Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat Rev Clin Oncol. 2017;14:463–82.
Larkin JMG, Yan Y, McArthur GA, Ascierto PA, Liszkay G, Maio M, et al. Update of progression-free survival (PFS) and correlative biomarker analysis from coBRIM: Phase III study of cobimetinib (cobi) plus vemurafenib (vem) in advanced BRAF-mutated melanoma. J Clin Oncol. 2015;33:9006–9006.
Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386:444–51.
Sullivan RJ, Flaherty KT. Resistance to BRAF-targeted therapy in melanoma. Eur J Cancer. 2013;49:1297–304.
Arozarena I, Wellbrock C. Phenotype plasticity as enabler of melanoma progression and therapy resistance. Nat Rev Cancer. 2019;19:377–91.
Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK, et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell. 2010;18:683–95.
Müller J, Krijgsman O, Tsoi J, Robert L, Hugo W, Song C, et al. Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma. Nat Commun. 2014;5:5712.
Hugo W, Shi H, Sun L, Piva M, Song C, Kong X, et al. Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. Cell. 2015;162:1271–85.
Hartman ML, Czyz M. MITF in melanoma: mechanisms behind its expression and activity. Cell Mol Life Sci. 2015;72:1249–60.
Basile KJ, Le K, Hartsough EJ, Aplin AE. Inhibition of mutant BRAF splice variant signaling by next-generation, selective RAF inhibitors. Pigment Cell Melanoma Res. 2014;27:479–84.
Du Z, Lovly CM. Mechanisms of receptor tyrosine kinase activation in cancer. Mol Cancer. 2018;17:58.
Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468:973–7.
Wagenaar TR, Ma L, Roscoe B, Park SM, Bolon DN, Green MR. Resistance to vemurafenib resulting from a novel mutation in the BRAFV600E kinase domain. Pigment Cell Melanoma Res. 2014;27:124–33.
Leitinger B. Molecular analysis of collagen binding by the human discoidin domain receptors, DDR1 and DDR2 identification of collagen binding sites in DDR2. J Biol Chem. 2003;278:16761–9.
Shrivastava A, Radziejewski C, Campbell E, Kovac L, McGlynn M, Ryan TE, et al. An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors. Mol Cell. 1997;1:25–34.
Vogel W, Gish GD, Alves F, Pawson T. The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell. 1997;1:13–23.
Valiathan RR, Marco M, Leitinger B, Kleer CG, Fridman R. Discoidin domain receptor tyrosine kinases: new players in cancer progression. Cancer Metastasis Rev. 2012;31:295–321.
Henriet E, Sala M, Abou Hammoud A, Tuariihionoa A, Di Martino J, Ros M, et al. Multitasking discoidin domain receptors are involved in several and specific hallmarks of cancer. Cell Adhes Migr. 2018;12:363–77.
Das S, Ongusaha PP, Yang YS, Park J-M, Aaronson SA, Lee SW. Discoidin domain receptor 1 receptor tyrosine kinase induces cyclooxygenase-2 and promotes chemoresistance through nuclear factor-kappaB pathway activation. Cancer Res. 2006;66:8123–30.
Ren T, Zhang J, Zhang J, Liu X, Yao L. Increased expression of discoidin domain receptor 2 (DDR2): a novel independent prognostic marker of worse outcome in breast cancer patients. Med Oncol. 2013;30:397.
El Azreq M-A, Kadiri M, Boisvert M, Pagé N, Tessier PA, Aoudjit F. Discoidin domain receptor 1 promotes Th17 cell migration by activating the RhoA/ROCK/MAPK/ERK signaling pathway. Oncotarget. 2016;7:44975–90.
Ongusaha PP, Kim J, Fang L, Wong TW, Yancopoulos GD, Aaronson SA, et al. p53 induction and activation of DDR1 kinase counteract p53-mediated apoptosis and influence p53 regulation through a positive feedback loop. EMBO J. 2003;22:1289–301.
Park J-W, Lee Y-S, Kim JS, Lee S-K, Kim BH, Lee JA, et al. Downregulation of discoidin domain receptor 2 decreases tumor growth of hepatocellular carcinoma. J Cancer Res Clin Oncol. 2015;141:1973–83.
Ren T, Zhang W, Liu X, Zhao H, Zhang J, Zhang J, et al. Discoidin domain receptor 2 (DDR2) promotes breast cancer cell metastasis and the mechanism implicates epithelial-mesenchymal transition programme under hypoxia. J Pathol. 2014;234:526–37.
Reger de Moura C, Battistella M, Sohail A, Caudron A, Feugeas JP, Podgorniak M-P, et al. Discoidin domain receptors: a promising target in melanoma. Pigment Cell Melanoma Res. 2019;32:697–707.
Badiola I, Villacé P, Basaldua I, Olaso E. Downregulation of discoidin domain receptor 2 in A375 human melanoma cells reduces its experimental liver metastasis ability. Oncol Rep. 2011;26:971–8.
Søndergaard JN, Nazarian R, Wang Q, Guo D, Hsueh T, Mok S, et al. Differential sensitivity of melanoma cell lines with BRAFV600E mutation to the specific Raf inhibitor PLX4032. J Transl Med. 2010;8:39.
Tsoi J, Robert L, Paraiso K, Galvan C, Sheu KM, Lay J, et al. Multi-stage differentiation defines melanoma subtypes with differential vulnerability to drug-induced iron-dependent oxidative stress. Cancer Cell. 2018;33:890–904. e5
Grither WR, Longmore GD. Inhibition of tumor–microenvironment interaction and tumor invasion by small-molecule allosteric inhibitor of DDR2 extracellular domain. Proc Natl Acad Sci USA. 2018;115:E7786–94.
Misek SA, Appleton KM, Dexheimer TS, Lisa beth EM, Lo RS.Larsen SD, et al. Rho-mediated signaling promotes BRAF inhibitor resistance in de-differentiated melanoma cells. Oncogene. 2019;39:1466–83..
Girard CA, Lecacheur M, Ben Jouira R, Berestjuk I, Diazzi S.Prod’homme V, et al. A feed-forward mechanosignaling loop confers resistance to therapies targeting the MAPK pathway in BRAF-mutant melanoma. Cancer Res. 2020;80:1927–41..
Day E, Waters B, Spiegel K, Alnadaf T, Manley PW, Buchdunger E, et al. Inhibition of collagen-induced discoidin domain receptor 1 and 2 activation by imatinib, nilotinib and dasatinib. Eur J Pharm. 2008;599:44–53.
Girotti MR, Pedersen M, Sanchez-Laorden B, Viros A, Turajlic S, Niculescu-Duvaz D, et al. Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma. Cancer Discov. 2013;3:158–67.
Xie B, Lin W, Ye J, Wang X, Zhang B, Xiong S, et al. DDR2 facilitates hepatocellular carcinoma invasion and metastasis via activating ERK signaling and stabilizing SNAIL1. J Exp Clin Cancer Res. 2015;34:101.
Wang Y-G, Xu L, Jia R-R, Wu Q, Wang T, Wei J, et al. DDR2 induces gastric cancer cell activities via activating mTORC2 signaling and is associated with clinicopathological characteristics of gastric cancer. Dig Dis Sci. 2016;61:2272–83.
Grither WR, Divine LM, Meller EH, Wilke DJ, Desai RA, Loza AJ, et al. TWIST1 induces expression of discoidin domain receptor2 (DDR2) to promote ovarian cancer metastasis. Oncogene. 2018;37:1714–29.
Hidalgo-Carcedo C, Hooper S, Chaudhry SI, Williamson P, Harrington K, Leitinger B, et al. Collective cell migration requires suppression of actomyosin at cell-cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6. Nat Cell Biol. 2011;13:49–58.
Axl-dependent signalling: a clinical update. - PubMed - NCBI [Internet]. [accessed 31 Mar 2020]. https://www.ncbi.nlm.nih.gov/pubmed/?term=Axl-dependent+signaling%3A+A+clinical+update
Keating GM. Dasatinib: a review in chronic myeloid leukaemia and Ph+ acute lymphoblastic leukaemia. Drugs. 2017;77:85–96.
Juin A, Di Martino J, Leitinger B, Henriet E, Gary A-S, Paysan L, et al. Discoidin domain receptor 1 controls linear invadosome formation via a Cdc42-Tuba pathway. J Cell Biol. 2014;207:517–33.
Rammal H, Saby C, Magnien K, Van-Gulick L, Garnotel R, Buache E, et al. Discoidin domain receptors: potential actors and targets in cancer. Front Pharmacol [Internet]. 2016 Mar [accessed 1 Sept 2019];7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789497/
Ambrogio C, Gómez-López G, Falcone M, Vidal A, Nadal E, Crosetto N, et al. Combined inhibition of DDR1 and Notch signaling is a therapeutic strategy for KRAS-driven lung adenocarcinoma. Nat Med. 2016;22:270–7.
Hammerman PS, Sos ML, Ramos AH, Xu C, Dutt A, Zhou W, et al. Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov. 2011;1:78–89.
Hedberg ML, Goh G, Chiosea SI, Bauman JE, Freilino ML, Zeng Y, et al. Genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma. J Clin Investig. 2016;126:169–80.
Kurashige J, Hasegawa T, Niida A, Sugimachi K, Deng N, Mima K, et al. Integrated molecular profiling of human gastric cancer identifies DDR2 as a potential regulator of peritoneal dissemination. Sci Rep. 2016;6:22371.
Wang L, Leite de Oliveira R, Huijberts S, Bosdriesz E, Pencheva N, Brunen D, et al. An acquired vulnerability of drug-resistant melanoma with therapeutic potential. Cell. 2018;173:1413–1425. e14
Gao M, Duan L, Luo J, Zhang L, Lu X, Zhang Y, et al. Discovery and optimization of 3-(2-(Pyrazolo[1,5-a]pyrimidin-6-yl)ethynyl)benzamides as novel selective and orally bioavailable discoidin domain receptor 1 (DDR1) inhibitors. J Med Chem. 2013;56:3281–95.
Kim H-G, Tan L, Weisberg EL, Liu F, Canning P, Choi HG, et al. Discovery of a potent and selective DDR1 receptor tyrosine kinase inhibitor. ACS Chem Biol. 2013;8:2145–50.
Juin A, Billottet C, Moreau V, Destaing O, Albiges-Rizo C, Rosenbaum J, et al. Physiological type I collagen organization induces the formation of a novel class of linear invadosomes. Schwarzbauer JE, editor. Mol Biol Cell. 2012;23:297–309.
Deutsch EW, Bandeira N, Sharma V, Perez-Riverol Y, Carver JJ, Kundu DJ, et al. The ProteomeXchange consortium in 2020: enabling ‘big data’ approaches in proteomics. Nucleic Acids Res. 2020;48:D1145–52.
Acknowledgements
We are grateful to Prof. Longmore for providing us with DDR2 inhibitors. Many thanks to Dr. David Santamaria for giving us advice on this project and for providing us with a list of MAP kinase targets and their associated primers. We are grateful to the Centre de Ressources Biologiques (CRB), Bordeaux, for access to melanoma patient samples.
Funding
This work is supported by Inca (PLBIO Inca, PLBIO15-135), SIRIC BRIO 2, Fondation de France, FRM, équipe labellisée (grant number DEQ20180839586). Margaux Sala is financed by a PhD grant from the French ministère supérieur de l’enseignement et de la recherche.
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MS, NA, AJ, MM, EH, AAH and AU performed experiments. SDT, JWD, AAR and CD ran proteomic assay. EG, JPM, APL, BV and AU helped with their clinical knowledge and expertise in melanoma. NDS performed the immunohistochemical-labelling studies. BR helped with the xenograft mouse model. STD and VM provided feedback about the experiments. MS and FS contributed to design and interpretation of the experiments and to the writing of the manuscript. FS coordinated the study. All authors have approved the final version of the paper.
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Sala, M., Allain, N., Moreau, M. et al. Discoidin Domain Receptor 2 orchestrates melanoma resistance combining phenotype switching and proliferation. Oncogene 41, 2571–2586 (2022). https://doi.org/10.1038/s41388-022-02266-1
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DOI: https://doi.org/10.1038/s41388-022-02266-1