Combination of MEK and SRC inhibition suppresses melanoma cell growth and invasion
Open accessAbstract
The RAS-RAF-MEK-ERK pathway is deregulated in over 90% of malignant melanomas, and targeting MEK as a central kinase of this pathway is currently tested in clinical trials. However, dose-limiting side effects are observed, and MEK inhibitors that sufficiently reduce ERK activation in patients show a low clinical response. Apart from dose limitations, a reason for the low response to MEK targeting drugs is thought to be the upregulation of counteracting signalling cascades as a direct response to MEK inhibition. Therefore, understanding the biology of melanoma cells and the effects of MEK inhibition on these cells will help to identify new combinatorial approaches that are more potent and allow for lower concentrations of the drug being used. We have discovered that in melanoma cells MEK inhibition by selumetinib (AZD6244, ARRY-142886) or PD184352, while efficiently suppressing proliferation, stimulates increased invasiveness. Inhibition of MEK suppresses actin-cortex contraction and increases integrin-mediated adhesion. Most importantly, and surprisingly, MEK inhibition results in a significant increase in matrix metalloproteases (MMP)-2 and membrane-type 1-MMP expression. All together, MEK inhibition in melanoma cells induces a 'mesenchymal' phenotype that is characterised by protease-driven invasion. This mode of invasion is dependent on integrin-mediated adhesion, and because SRC kinases are the main regulators of this process, the SRC kinase inhibitor, saracatinib (AZD0530), completely abolished the MEK inhibitor-induced invasion. Moreover, the combination of saracatinib and selumetinib effectively suppressed the growth and invasion of melanoma cells in a 3D environment, suggesting that combined inhibition of MEK and SRC is a promising approach to improve the efficacy of targeting the ERK/MAP kinase pathway in melanoma.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Drug combinations of MEK and SRC inhibitors have been carried out in vitro using various types of cancer cell lines and to a less degree in vivo using mouse models, where enhanced anti-cancer effects have been reported.
“Notably, exploration of drug combinations of MEK and SRC inhibitors have been carried out in vitro using various types of cancer cell lines and to a less degree in vivo using mouse models, where enhanced anti-cancer effects have been reported [53–57].”
From An integrative gene expression signature analysis identifies CMS4 KRAS-mutated colorectal cancers sensitive to combined MEK and SRC targeted therapy (2022) · cites this paper as [56]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma
Bollag, G. E., Hirth, P., Tsai, J. Y., Zhang, J., Ibrahim, P. N., Cho, H., Spevak, W. R., Zhang, C., Zhang, Y., Habets, G. G. M., et al. (2010) · Nature · doi:10.1038/nature09454 · Cited by 1,837 · see citing works
Kinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF
Heidorn, S. J., Milagre, C. S., Whittaker, S. R., Nourry, A., Niculescu‐Duvaz, I., Dhomen, N. S., Hussain, J., Reis-Filho, J. S., Springer, C. J., Pritchard, C. A., et al. (2010) · Cell · doi:10.1016/j.cell.2009.12.040 · Cited by 1,468 · see citing works
Compensation mechanism in tumor cell migration
Wolf, K., Mazo, I. B., Leung, H. C. H., Engelke, K., von Andrian, U. H., Deryugina, E. I., Strongin, A. Y., Bröcker, E., & Friedl, P. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200209006 · Cited by 1,392 · see citing works
Regulation of Cell Motility by Mitogen-activated Protein Kinase
Klemke, R. L., Cai, S., Giannini, A. L. M., Gallagher, P. J., de Lanerolle, P., & Cheresh, D. A. (1997) · The Journal of Cell Biology · doi:10.1083/jcb.137.2.481 · Cited by 1,235 · see citing works
Sahai, E. A., & Marshall, C. J. (2003) · Nature Cell Biology · doi:10.1038/ncb1019 · Cited by 1,148 · see citing works
Rac Activation and Inactivation Control Plasticity of Tumor Cell Movement
Sanz‐Moreno, V., Gadéa, G., Ahn, J., Paterson, H., Marra, P., Pinner, S. E., Sahai, E. A., & Marshall, C. J. (2008) · Cell · doi:10.1016/j.cell.2008.09.043 · Cited by 959 · see citing works
Sabeh, F., Shimizu‐Hirota, R., & Weiss, S. J. (2009) · The Journal of Cell Biology · doi:10.1083/jcb.200807195 · Cited by 658 · see citing works
Akiyama, S. K., Yamada, S. S., Chen, W. T., & Yamada, K. M. (1989) · The Journal of Cell Biology · doi:10.1083/jcb.109.2.863 · Cited by 612 · see citing works
Cell motility through plasma membrane blebbing
Fackler, O., & Grosse, R. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200802081 · Cited by 588 · see citing works
Yeh, T. C., Marsh, V., Bernat, B. A., Ballard, J., Colwell, H., Evans, R. J., Parry, J., Smith, D. J., Brandhuber, B. J., Gross, S. D., et al. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-1150 · Cited by 583 · see citing works
Rho signaling, ROCK and mDia1, in transformation, metastasis and invasion
Narumiya, S., Tanji, M., & Ishizaki, T. (2009) · Cancer and Metastasis Reviews · doi:10.1007/s10555-008-9170-7 · Cited by 530 · see citing works
The interplay between Src and integrins in normal and tumor biology
Playford, M. P., & Schaller, M. D. (2004) · Oncogene · doi:10.1038/sj.onc.1208080 · Cited by 520 · see citing works
Smalley, K. S. M., Haass, N. K., Brafford, P. A., Lioni, M., Flaherty, K. T., & Herlyn, M. (2006) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-06-0084 · Cited by 459 · see citing works
Itoh, Y., Takamura, A., Ito, N., Maru, Y., Sato, H., Suenaga, N., Aoki, T., & Seiki, M. (2001) · The EMBO Journal · doi:10.1093/emboj/20.17.4782 · Cited by 399 · see citing works
Hennequin, L. F., Allen, J. M., Breed, J., Curwen, J., Fennell, M., Green, T. P., der Brempt, C. L., Morgentin, R., Norman, R. A., Olivier, A., et al. (2006) · Journal of Medicinal Chemistry · doi:10.1021/jm060434q · Cited by 365 · see citing works
Glading, A., Bodnar, R. J., Reynolds, I. J., Shiraha, H., Satish, L., Potter, D. A., Blair, H. C., & Wells, A. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.6.2499-2512.2004 · Cited by 271 · see citing works
Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530
Green, T. P., Fennell, M., Whittaker, R., Curwen, J., Jacobs, V., Allen, J., Logie, A., Hargreaves, J., Hickinson, D. M., Wilkinson, R. W., et al. (2009) · Molecular Oncology · doi:10.1016/j.molonc.2009.01.002 · Cited by 238 · see citing works
Gopal, Y. N. V., Deng, W., Woodman, S. E., Komurov, K., Ram, P. T., Smith, P. D., & Davies, M. A. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0902 · Cited by 229 · see citing works
Arozarena, I., Sánchez‐Laorden, B. L., Packer, L., Hidalgo-Carcedo, C., Hayward, R., Virós, A., Sahai, E. A., & Marais, R. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.10.029 · Cited by 212 · see citing works
Self-citationA Novel Role for FAK as a Protease-Targeting Adaptor Protein
Carragher, N. O., Westhoff, M., Fincham, V. J., Schaller, M. D., & Frame, M. C. (2003) · Current Biology · doi:10.1016/s0960-9822(03)00544-x · Cited by 198 · see citing works
BRAF as therapeutic target in melanoma
Wellbrock, C., & Hurlstone, A. F. L. (2010) · Biochemical Pharmacology · doi:10.1016/j.bcp.2010.03.019 · Cited by 177 · see citing works
Self-citationSrc and focal adhesion kinase as therapeutic targets in cancer
Brunton, V. G., & Frame, M. C. (2008) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2008.06.012 · Cited by 177 · see citing works
MT1‐MMP: A key regulator of cell migration in tissue
Itoh, Y. (2006) · IUBMB Life · doi:10.1080/15216540600962818 · Cited by 176 · see citing works
Zheng, Y., Xia, Y., Hawke, D. H., Hallé, M., Tremblay, M. L., Gao, X., Zhou, X. Z., Aldape, K., Cobb, M. H., Xie, K., et al. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.06.013 · Cited by 174 · see citing works
Carragher, N. O., Walker, S. M., Carragher, L., Harris, F. M., Sawyer, T. K., Brunton, V., Ozanne, B. W., & Frame, M. C. (2006) · Oncogene · doi:10.1038/sj.onc.1209582 · Cited by 164 · see citing works
A phase 2 trial of dasatinib in advanced melanoma
Kluger, H. M., Dudek, A. Z., McCann, C., Ritacco, J., Southard, N. Z., Jilaveanu, L. B., Molinaro, A. M., & Sznol, M. (2010) · Cancer · doi:10.1002/cncr.25766 · Cited by 155 · see citing works
Dual Regulation of MMP-2 Expression by the Type 1 Insulin-like Growth Factor Receptor
Zhang, D., Bar‐Eli, M., Meloche, S., & Brodt, P. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m313145200 · Cited by 152 · see citing works
Dummer, R., Robert, C., Chapman, P. B., Sosman, J. A., Middleton, M. R., Bastholt, L., Kemsley, K., Cantarini, M., Morris, C., & Kirkwood, J. M. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2008.26.15_suppl.9033 · Cited by 132 · see citing works
Isoform specific function of calpain 2 in regulating membrane protrusion
Franco, S. J., Perrin, B. J., & Anna Huttenlocher, A. (2004) · Experimental Cell Research · doi:10.1016/j.yexcr.2004.05.021 · Cited by 130 · see citing works
Buettner, R., Mesa, T., Vultur, A., Lee, F., & Jove, R. (2008) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-08-0169 · Cited by 123 · see citing works
In melanoma, beta-catenin is a suppressor of invasion
Arozarena, I., Bischof, H., Gilby, D. C., Belloni, B., Dummer, R., & Wellbrock, C. (2011) · Oncogene · doi:10.1038/onc.2011.162 · Cited by 122 · see citing works
Self-citationmda -9/Syntenin promotes metastasis in human melanoma cells by activating c-Src
Boukerche, H., Su, Z.-Z., Prévot, C., Sarkar, D., & Fisher, P. B. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808171105 · Cited by 109 · see citing works
p190RhoGAP is the convergence point of adhesion signals from α5β1 integrin and syndecan-4
Bass, M. D., Morgan, M. R., Roach, K. A., et al. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200711129 · Cited by 105 · see citing works
Yan, C., Wang, H., & Boyd, D. D. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m112069200 · Cited by 96 · see citing works
Preclinical evaluation of dasatinib, a potent Src kinase inhibitor, in melanoma cell lines
Eustace, A. J., Crown, J. P., CLYNES, M. M., & O’Donovan, N. (2008) · Journal of Translational Medicine · doi:10.1186/1479-5876-6-53 · Cited by 95 · see citing works
Wellbrock, C., Weisser, C., Geissinger, E., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m110684200 · Cited by 92 · see citing works
Self-citationJohnson, M. L., Riely, G. J., Rizvi, N. A., Azzoli, C. G., Kris, M. G., Sima, C. S., Ginsberg, M. S., Pao, W. J., & Miller, V. A. (2011) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e3182161508 · Cited by 91 · see citing works
Geissinger, E., Weisser, C., Fischer, P., et al. (2002) · PubMed · Cited by 89 · see citing works
Lee, S.-H., Bahn, J. H., Whitlock, N. C., & Baek, S. J. (2010) · Oncogene · doi:10.1038/onc.2010.251 · Cited by 79 · see citing works
Cooperative Roles of Fyn and Cortactin in Cell Migration of Metastatic Murine Melanoma
Huang, J., Asawa, T., Takato, T., & Sakai, R. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m308213200 · Cited by 73 · see citing works
Yang, J.-Y., Chang, C.-J., Xia, W., Wang, Y., Wong, K., Engelman, J. A., Du, Y., Andreeff, M., Hortobágyi, G. N., & Hung, M. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-4524 · Cited by 69 · see citing works
Src activation in melanoma and Src inhibitors as therapeutic agents in melanoma
Homsi, J., Cubitt, C. L., Zhang, S., Münster, P. N., Yu, H., Sullivan, D. M., Jove, R., Messina, J. L., & DAUD, A. I. (2009) · Melanoma Research · doi:10.1097/cmr.0b013e328304974c · Cited by 67 · see citing works
Tower, G. B., Coon, C. C., Benbow, U., Vincenti, M. P., & Brinckerhoff, C. (2002) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/s0925-4439(01)00105-3 · Cited by 65 · see citing works
A phase I study of dasatinib and weekly paclitaxel for metastatic breast cancer
Fornier, M. N., Morris, P. G., Abbruzzi, A., D’Andrea, G. M., Gilewski, T., Bromberg, J., Dang, C. T., Dickler, M. N., Modi, S., Seidman, A. D., et al. (2011) · Annals of Oncology · doi:10.1093/annonc/mdr018 · Cited by 64 · see citing works
Meierjohann, S., Hufnagel, A., Wende, E., et al. (2010) · Molecular Cancer · doi:10.1186/1476-4598-9-201 · Cited by 63 · see citing works
Renouf, D. J., Moore, M. J., Hedley, D. W., Gill, S., Jonker, D. J., Chen, E. X., Walde, D., Goel, R., Southwood, B., Gauthier, I. C., et al. (2010) · Investigational New Drugs · doi:10.1007/s10637-010-9611-3 · Cited by 53 · see citing works
Elevated c-Src and c-Yes expression in malignant skin cancers
Lee, J. H., Pyon, J.-K., Kim, D. W., et al. (2010) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/1756-9966-29-116 · Cited by 46 · see citing works
Pullikuth, A., & Catling, A. D. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.01178-09 · Cited by 38 · see citing works
Biological challenges of BRAF inhibitor therapy
Puzanov, I. J., Burnett, P., & Flaherty, K. T. (2011) · Molecular Oncology · doi:10.1016/j.molonc.2011.01.005 · Cited by 36 · see citing works
Wellbrock, C., & Schartl, M. (2000) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2000.01378.x · Cited by 35 · see citing works
Self-citationBalkovetz, D. F. (1998) · Microscopy Research and Technique · doi:10.1002/(sici)1097-0029(19981201)43:5 · Cited by 27 · see citing works
Dong, M., Rice, L. P., Lepler, S. E., Pampo, C., & Siemann, D. W. (2010) · PubMed · Cited by 23 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Simpkins, F., Jang, K., Yoon, H., Hew, K. E., Kim, M., Azzam, D. J., Sun, J., Zhao, D., Ince, T. A., Liu, W., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-3697 · Cited by 67 · see citing works
Yuan, M., Xu, L.-F., Zhang, J., Kong, S.-Y., Wu, M., Lao, Y.-Z., Zhou, H., Zhang, L., & Xu, H. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00586 · Cited by 26 · see citing works
Yang, M., Davis, T. B., Pflieger, L., Nebozhyn, M. V., Loboda, A., Wang, H., Schell, M. J., Thota, R., Pledger, W. J., & Yeatman, T. J. (2022) · BMC Cancer · doi:10.1186/s12885-022-09344-3 · Cited by 22 · see citing works
- Authors
- Ferguson, J., Arozarena, I., Ehrhardt, M., & Wellbrock, C.
- Affiliations
- Wellcome Centre for Cell-Matrix Research (GB)
- Corresponding author
- Wellbrock, C
- Venue
- Oncogene
- Published
- 2012-02-06
- Volume
- 32
- Issue
- 1
- Pages
- 86-96
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC3378628
- OpenAlex
- W2110217188
- Cited by
- 68
- References
- 52
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 4 · 2021: 3 · 2020: 3 · 2019: 6 · 2018: 6 · 2017: 9 · 2016: 3 · 2015: 9 · 2014: 3 · 2013: 10 · 2012: 4
- FWCI
- 3.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- University of Huddersfield Repository (University of Huddersfield) (submittedVersion)
- Funders
- Cancer Research UK (C11591/A10202)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- melanoma, MEK inhibition, Src kinase inhibition, selumetinib, saracatinib, RAS/MAPK pathway, tumor invasion, mesenchymal phenotype, MMP-2, membrane-type 1 MMP, integrin-mediated adhesion, combination therapy, 3D tumor growth
- MeSH terms
- Benzimidazoles, Cell Adhesion, Cell Division, Collagen, Humans, Melanoma, Neoplasm Invasiveness, Quinazolines, Integrin beta1, src-Family Kinases, MAP Kinase Kinase Kinases, Protein Kinase Inhibitors, Benzodioxoles
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
