Cited by 1,771Melanoma and MAPK PathwaysCancer Cells and MetastasisColorectal Cancer Treatments and Studies

The DOI matches its Crossref record; 31 of the 31 references it cites were found in a registry or an index.

Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion

Open access

Straussman, Ravid, Morikawa, Teppei, Shee, Kevin, Barzily-Rokni, Michal, Qian, Zhi Rong, Du, Jinyan, Davis, Ashli, Mongare, Margaret M., Gould, Joshua, Frederick, Dennie T., Cooper, Zachary A., Chapman, Paul B., Solit, David B., Ribas, Antoni, Lo, Roger S., Flaherty, Keith T., Ogino, Shuji, Wargo, Jennifer A., Golub, Todd R.·2012·Nature

DOI 10.1038/nature11183PMC PMC3711467

Open this paper in CoChat — free account

Abstract

Drug resistance presents a challenge to the treatment of cancer patients. Many studies have focused on cell-autonomous mechanisms of drug resistance. By contrast, we proposed that the tumour micro-environment confers innate resistance to therapy. Here we developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs. We found that stroma-mediated resistance is common, particularly to targeted agents. We characterized further the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibitors because most patients with this type of cancer show some degree of innate resistance. Proteomic analysis showed that stromal cell secretion of hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI(3)K)–AKT signalling pathways, and immediate resistance to RAF inhibition. Immunohistochemistry experiments confirmed stromal cell expression of HGF in patients with BRAF-mutant melanoma and showed a significant correlation between HGF expression by stromal cells and innate resistance to RAF inhibitor treatment. Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. More generally, this study indicates that the systematic dissection of interactions between tumours and their micro-environment can uncover important mechanisms underlying drug resistance.

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

Crossref · 10.1038/nature11183

Cites

31 of 31 references verified0 citation errors · 0 not checkable

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?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Improved survival with vemurafenib in melanoma with BRAF V600E mutation
Chapman, P. B., Hauschild, A., Robert, C., Haanen, J. B., Ascierto, P., Larkin, J., Dummer, R., Garbe, C., Testori, A., Maio, M., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1103782 · Cited by 7,720
Self-citation
Fibroblasts in cancer
Kalluri, R., & Zeisberg, M. (2006) · Nature Reviews Cancer · doi:10.1038/nrc1877 · Cited by 4,538
MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling
Engelman, J. A., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J. O., Lindeman, N., Gale, C.-M., Zhao, X., Christensen, J., et al. (2007) · Science · doi:10.1126/science.1141478 · Cited by 4,496
Microenvironmental regulation of metastasis
Joyce, J. A., & Pollard, J. W. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2618 · Cited by 3,684
Inhibition of Mutated, Activated BRAF in Metastatic Melanoma
Flaherty, K. T., Puzanov, I., Kim, K. B., Ribas, A., McArthur, G. A., Sosman, J. A., O'Dwyer, P. J., Lee, R. J., Grippo, J. F., Nolop, K., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1002011 · Cited by 3,103
Self-citation
Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation
Nazarian, R., Shi, H., Wang, Q., Kong, X., Koya, R. C., Lee, H., Chen, Z., Lee, M., Attar, N., Sazegar, H., et al. (2010) · Nature · doi:10.1038/nature09626 · Cited by 2,244
Self-citation
Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib
Sosman, J. A., Kim, K. B., Schuchter, L., Gonzalez, R., Pavlick, A. C., Weber, J. S., McArthur, G. A., Hutson, T. E., Moschos, S. J., Flaherty, K. T., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1112302 · Cited by 2,156
Self-citation
Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR
Prahallad, A., Sun, C., Huang, S., Di Nicolantonio, F., Salazar, R., Zecchin, D., Beijersbergen, R. L., Bardelli, A., & Bernards, R. (2012) · Nature · doi:10.1038/nature10868 · Cited by 2,051
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 1,875
Self-citation
COT drives resistance to RAF inhibition through MAP kinase pathway reactivation
Johannessen, C. M., Boehm, J. S., Kim, S. Y., Thomas, S. R., Wardwell, L., Johnson, L. A., Emery, C. M., Stransky, N., Cogdill, A. P., Barretina, J., et al. (2010) · Nature · doi:10.1038/nature09627 · Cited by 1,460
Self-citation

Show all 30 references

Sorted by citations

Items 401–500 of 1,001

The HGF/c-MET Pathway Is a Driver and Biomarker of VEGFR-inhibitor Resistance and Vascular Remodeling in Non–Small Cell Lung Cancer
Cascone, T., Xu, L., Lin, H. Y., Liu, W., Tran, H. T., Liu, Y., Howells, K., Haddad, V., Hanrahan, E. O., Nilsson, M. B., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-3216 · Cited by 92
Network propagation in the cytoscape cyberinfrastructure
Carlin, D. E., Demchak, B., Pratt, D. R., Sage, E., & Ideker, T. (2017) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1005598 · Cited by 90
Structural basis for the activation of PLC-γ isozymes by phosphorylation and cancer-associated mutations
Hajicek, N., Keith, N. C., Siraliev-Perez, E., Temple, B. R., Huang, W., Zhang, Q., Harden, T. K., & Sondek, J. (2019) · eLife · doi:10.7554/elife.51700 · Cited by 89
Functional diversity of cancer‐associated fibroblasts in modulating drug resistance
Bu, L., Baba, H., Yasuda, T., Uchihara, T., & Ishimoto, T. (2020) · Cancer Science · doi:10.1111/cas.14578 · Cited by 85
Resistance mechanisms to targeted therapy in BRAF-mutant melanoma - A mini review
Tangella, L. P., Clark, M. E., & Gray, E. S. (2020) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2020.129736 · Cited by 92
MITF Modulates Therapeutic Resistance through EGFR Signaling
Ji, Z., Chen, Y. E., Kumar, R., Taylor, M., Njauw, C.-N. J., Miao, B., Frederick, D. T., Wargo, J. A., Flaherty, K. T., Jonsson, G. G., et al. (2015) · Journal of Investigative Dermatology · doi:10.1038/jid.2015.105 · Cited by 87
Self-citation
Fibronectin induction abrogates the BRAF inhibitor response of BRAF V600E/PTEN-null melanoma cells
Fedorenko, I. V., Abel, E. V., Koomen, J. M., Fang, B., Wood, E. R., Chen, Y. A., Fisher, K. J., Iyengar, S., Dahlman, K. B., Wargo, J. A., et al. (2015) · Oncogene · doi:10.1038/onc.2015.188 · Cited by 85
Self-citation
The Impact of Microenvironmental Heterogeneity on the Evolution of Drug Resistance in Cancer Cells
Mumenthaler, S. M., Foo, J., Choi, N. C., Heise, N., Leder, K., Agus, D. B., Pao, W. J., Michor, F., & Mallick, P. (2015) · Cancer Informatics · doi:10.4137/cin.s19338 · Cited by 83
Stromal-derived IGF2 promotes colon cancer progression via paracrine and autocrine mechanisms
Unger, C., Kramer, N., Unterleuthner, D., Scherzer, M., Burian, A., Rudisch, A., Stadler, M., Schlederer, M., Lenhardt, D., Riedl, A., et al. (2017) · Oncogene · doi:10.1038/onc.2017.116 · Cited by 85
Single-cell transcriptome-based multilayer network biomarker for predicting prognosis and therapeutic response of gliomas
Zhang, J., Guan, M., Wang, Q., Zhang, J., Zhou, T., & Sun, X. (2019) · Briefings in Bioinformatics · doi:10.1093/bib/bbz040 · Cited by 85
Melanoma: Molecular genetics, metastasis, targeted therapies, immunotherapies, and therapeutic resistance
Wagstaff, W., Mwamba, R. N., Grullon, K., Armstrong, M. L., Zhao, P., Hendren-Santiago, B. K., Qin, K. H., Li, A. J., Hu, D. A., Youssef, A., et al. (2022) · Genes & Diseases · doi:10.1016/j.gendis.2022.04.004 · Cited by 94
Emerging concepts in pancreatic cancer medicine: targeting the tumor stroma
Neeße, A., Gress, T. M., Tuveson, D. A., Michl, P., & Krug, S. (2013) · OncoTargets and Therapy · doi:10.2147/ott.s38111 · Cited by 87
Compensatory Pathways in Oncogenic Kinase Signaling and Resistance to Targeted Therapies: Six Degrees of Separation
Trusolino, L., & Bertotti, A. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0400 · Cited by 86
Targeting the HGF/MET Axis in Cancer Therapy: Challenges in Resistance and Opportunities for Improvement
Huang, X., Li, E., Shen, H., Wang, X., Tang, T., Zhang, X., Xu, J., Tang, Z., Guo, C., Bai, X., et al. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00152 · Cited by 82
The nuclear oncoprotein Fra-1: a transcription factor knocking on therapeutic applications’ door
Talotta, F., Casalino, L., & Verde, P. (2020) · Oncogene · doi:10.1038/s41388-020-1306-4 · Cited by 84
Mechanisms of resistance to tyrosine kinase inhibitor‐targeted therapy and overcoming strategies
Ou, X., Gao, G., Habaz, I. A., & Wang, Y. (2024) · MedComm · doi:10.1002/mco2.694 · Cited by 104
Cancer-Associated Fibroblasts: Perspectives in Cancer Therapy
Prakash, J. (2016) · Trends in cancer · doi:10.1016/j.trecan.2016.04.005 · Cited by 84
Dermal fibroblast expression of stromal cell-derived factor-1 (SDF-1) promotes epidermal keratinocyte proliferation in normal and diseased skin
Quan, C., Cho, M. K., Shao, Y., Mianecki-Morton, L., Liao, E. A., Perry, D., & Quan, T. (2015) · Protein & Cell · doi:10.1007/s13238-015-0198-5 · Cited by 82
Microenvironment-Derived HGF Overcomes Genetically Determined Sensitivity to Anti-MET Drugs
Pennacchietti, S., Cazzanti, M., Bertotti, A., Rideout, W. M., Han, M., Gyuris, J., Perera, T. P. S., Comoglio, P. M., Trusolino, L., & Michieli, P. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0761 · Cited by 83
Genetically engineered mouse models of melanoma
Pérez‐Guijarro, E., Day, C., Merlino, G. T., & Zaidi, M. R. (2017) · Cancer · doi:10.1002/cncr.30684 · Cited by 91
ERK-mediated phosphorylation regulates SOX10 sumoylation and targets expression in mutant BRAF melanoma
Han, S., Ren, Y., He, W., Liu, H., Zhi, Z., Zhu, X., Yang, T., Rong, Y., Ma, B., Purwin, T. J., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-02354-x · Cited by 85
Anti-EGFR Therapy Induces EGF Secretion by Cancer-Associated Fibroblasts to Confer Colorectal Cancer Chemoresistance
Garvey, C. M., Lau, R., Sanchez, A., Sun, R., Fong, E. J., Doche, M. E., Chen, O., Jusuf, A., Lenz, H., Larson, B. K., et al. (2020) · Cancers · doi:10.3390/cancers12061393 · Cited by 83
Translational Horizons in the Tumor Microenvironment: Harnessing Breakthroughs and Targeting Cures
Sun, Y. (2015) · Medicinal Research Reviews · doi:10.1002/med.21338 · Cited by 85
Antiproliferative Effects of Continued Mitogen-Activated Protein Kinase Pathway Inhibition following Acquired Resistance to BRAF and/or MEK Inhibition in Melanoma
Carlino, M. S., Gowrishankar, K., Saunders, C. A. B., Pupo, G. M., Snoyman, S., Zhang, X. D., Saw, R. P. M., Becker, T. M., Kefford, R. F., Long, G. V., et al. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-13-0011 · Cited by 82
Ipilimumab, Vemurafenib, Dabrafenib, and Trametinib: Synergistic Competitors in the Clinical Management of BRAF Mutant Malignant Melanoma
Luke, J. J., & Hodi, F. S. (2013) · The Oncologist · doi:10.1634/theoncologist.2012-0391 · Cited by 84
BRAFV600E Kinase Domain Duplication Identified in Therapy-Refractory Melanoma Patient-Derived Xenografts
Kemper, K., Krijgsman, O., Kong, X., Cornelissen‐Steijger, P., Shahrabi, A., Weeber, F., Velden, D. L. V. D., Bleijerveld, O. B., Kuilman, T., Kluin, R. J. C., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.05.064 · Cited by 81
Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2
Smith, B. D., Kaufman, M. D., Leary, C. B., Turner, B. A., Wise, S., Ahn, Y. M., Booth, R. J., Caldwell, T. M., Ensinger, C. L., Hood, M. M., et al. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-1105 · Cited by 82
Hepatocyte growth factor and Met in drug discovery
Sakai, K., Aoki, S., & Matsumoto, K. (2015) · The Journal of Biochemistry · doi:10.1093/jb/mvv027 · Cited by 82
Emerging Roles of SIRT1 in Cancer Drug Resistance
Wang, Z., & Chen, W. (2013) · Genes & Cancer · doi:10.1177/1947601912473826 · Cited by 87
Cisplatin-induced mesenchymal stromal cells-mediated mechanism contributing to decreased antitumor effect in breast cancer cells
Miklikova, S., Matúšková, M., Boháč, M., Toro, L., Durinikova, E., Tyčiaková, S., Demková, L., Gurský, J., & Kučerová, L. (2016) · Cell Communication and Signaling · doi:10.1186/s12964-016-0127-0 · Cited by 82
Analysis of 1,115 Patients Tested for MET Amplification and Therapy Response in the MD Anderson Phase I Clinic
Jardim, D. L. F., Tang, C. Z., Gagliato, D. D. M., Falchook, G. S., Hess, K. R., Jankú, F., Fu, S., Wheler, J. J., Zinner, R., Naing, A., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-1293 · Cited by 81
Control of NF ‐ kB activity in human melanoma by bromodomain and extra‐terminal protein inhibitor I ‐ BET 151
Gallagher, S. J., Mijatov, B., Gunatilake, D., Gowrishankar, K., Tiffen, J. C., James, W. F., Jin, L., Pupo, G. M., Cullinane, C. M., McArthur, G. A., et al. (2014) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12282 · Cited by 82
Targeting acetylcholine signaling modulates persistent drug tolerance in EGFR-mutant lung cancer and impedes tumor relapse
Nie, M., Chen, N., Pang, H., Jiang, T., Jiang, W., Tian, P., Yao, L., Chen, Y., DeBerardinis, R. J., Li, W., et al. (2022) · Journal of Clinical Investigation · doi:10.1172/jci160152 · Cited by 83
Mixed lineage kinases activate MEK independently of RAF to mediate resistance to RAF inhibitors
Marusiak, A. A., Edwards, Z. C., Hugo, W., Trotter, E. W., Girotti, M. R., Stephenson, N. L., Kong, X., Gartside, M. G., Fawdar, S., Hudson, A., et al. (2014) · Nature Communications · doi:10.1038/ncomms4901 · Cited by 86
Self-citation
Tensin-4-Dependent MET Stabilization Is Essential for Survival and Proliferation in Carcinoma Cells
Muharram, G., Sahgal, P., Korpela, T., Franceschi, N. D., Kaukonen, R., Clark, K., Tulasne, D., Carpén, O., & Ivaska, J. (2014) · Developmental Cell · doi:10.1016/j.devcel.2014.03.024 · Cited by 81
Role of c-MET Inhibitors in Overcoming Drug Resistance in Spheroid Models of Primary Human Pancreatic Cancer and Stellate Cells
Firuzi, O., Pei, P., Hassouni, B. E., Buijs, M., Coppola, S., Löhr, M. J., Funel, N., Heuchel, R. L., Carnevale, I., Schmidt, T., et al. (2019) · Cancers · doi:10.3390/cancers11050638 · Cited by 85
Oxidative Stress-Related Mechanisms in Melanoma and in the Acquired Resistance to Targeted Therapies
Pizzimenti, S., Ribero, S., Cucci, M. A., Grattarola, M., Monge, C., Dianzani, C., Barrera, G., & Muzio, G. (2021) · Antioxidants · doi:10.3390/antiox10121942 · Cited by 79
Dynamics of Chemokine, Cytokine, and Growth Factor Serum Levels in BRAF-Mutant Melanoma Patients during BRAF Inhibitor Treatment
Wilmott, J. S., Haydu, L. E., Menzies, A. M., Lum, T., Hyman, J., Thompson, J. F., Hersey, P., Kefford, R. F., Scolyer, R. A., & Long, G. V. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1302616 · Cited by 78
Single Inhibitors versus Dual Inhibitors: Role of HDAC in Cancer
Roy, R., Ria, T., RoyMahapatra, D., & Sk, U. H. (2023) · ACS Omega · doi:10.1021/acsomega.3c00222 · Cited by 79
Cancer-Associated Fibroblasts Promote the Chemo-resistance in Gastric Cancer through Secreting IL-11 Targeting JAK/STAT3/Bcl2 Pathway
Ma, J., Song, X., Xu, X., & Mou, Y. (2018) · Cancer Research and Treatment · doi:10.4143/crt.2018.031 · Cited by 78
Exosomic microRNAs in the Tumor Microenvironment
Neviani, P., & Fabbri, M. (2015) · Frontiers in Medicine · doi:10.3389/fmed.2015.00047 · Cited by 78
B-Raf Inhibition in the Clinic: Present and Future
Fiskus, W. C., & Mitsiades, N. (2016) · Annual Review of Medicine · doi:10.1146/annurev-med-090514-030732 · Cited by 79
Understanding Drug Sensitivity and Tackling Resistance in Cancer
Tyner, J. W., Haderk, F., Kumaraswamy, A., Baughn, L. B., Ness, B. V., Liu, S., Marathe, H., Alumkal, J. J., Bivona, T. G., Chan, K. S., et al. (2022) · Cancer Research · doi:10.1158/0008-5472.can-21-3695 · Cited by 81
Cancer-associated fibroblast-induced lncRNA UPK1A-AS1 confers platinum resistance in pancreatic cancer via efficient double-strand break repair
Zhang, X., Zheng, S., Hu, C., Li, G., Lin, H., Xia, R., Ye, Y., He, R., Li, Z., Lin, Q., et al. (2022) · Oncogene · doi:10.1038/s41388-022-02253-6 · Cited by 80
IGF-binding proteins secreted by cancer-associated fibroblasts induce context-dependent drug sensitization of lung cancer cells
Rix, L. L. R., Sumi, N. J., Hu, Q., Desai, B., Bryant, A. T., Li, X., Welsh, E. A., Fang, B., Kinose, F., Kuenzi, B. M., et al. (2022) · Science Signaling · doi:10.1126/scisignal.abj5879 · Cited by 76
The strategies to cure cancer patients by eradicating cancer stem-like cells
Mai, Y., Su, J., Yang, C., Xia, C., & Fu, L. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01867-y · Cited by 78
Inflammation-Induced Plasticity in Melanoma Therapy and Metastasis
Hölzel, M., & Tüting, T. (2016) · Trends in Immunology · doi:10.1016/j.it.2016.03.009 · Cited by 80
Heterogeneous Stromal Signaling within the Tumor Microenvironment Controls the Metastasis of Pancreatic Cancer
Rucki, A. A., Foley, K., Zhang, P., Xiao, Q., Kleponis, J., Wu, A. A., Sharma, R. B., Mo, G., Liu, A., Eyk, J. E. V., et al. (2016) · Cancer Research · doi:10.1158/0008-5472.can-16-1383 · Cited by 77
Resistance to RAF Inhibitors Revisited
Hartsough, E. J., Shao, Y., & Aplin, A. E. (2013) · Journal of Investigative Dermatology · doi:10.1038/jid.2013.358 · Cited by 82
Phosphoproteomics Reveals MAPK Inhibitors Enhance MET- and EGFR-Driven AKT Signaling in KRAS -Mutant Lung Cancer
Kim, J., Welsh, E. A., Fang, B., Bai, Y., Kinose, F., Eschrich, S. A., Koomen, J. M., & Haura, E. B. (2016) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-15-0506 · Cited by 76
Hgf/Met activation mediates resistance to BRAF inhibition in murine anaplastic thyroid cancers
Knauf, J. A., Luckett, K. A., Chen, K.-Y., Voza, F. A., Socci, N. D., Ghossein, R. A., & Fagin, J. A. (2018) · Journal of Clinical Investigation · doi:10.1172/jci120966 · Cited by 77
Status of Agents Targeting the HGF/c-Met Axis in Lung Cancer
Miranda, O., Farooqui, M., & Siegfried, J. M. (2018) · Cancers · doi:10.3390/cancers10090280 · Cited by 76
Towards Structural Systems Pharmacology to Study Complex Diseases and Personalized Medicine
Xie, L., Ge, X., Tan, H., Xie, L., Zhang, Y., Hart, T. D., Yang, X., & Bourne, P. E. (2014) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003554 · Cited by 75
Roles of tumor heterogeneity in the development of drug resistance: A call for precision therapy
Wu, D., Wang, D. C., Cheng, Y., Qian, M., Zhang, M., Shen, Q., & Wang, X. (2016) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2016.11.006 · Cited by 77
Cancer drug resistance: A fleet to conquer
Hussain, S., Singh, A., Nazir, S. U., Tulsyan, S., Khan, A., Kumar, R., Bashir, N., Tanwar, P., & Mehrotra, R. (2019) · Journal of Cellular Biochemistry · doi:10.1002/jcb.28782 · Cited by 80
Combined Pan-RAF and MEK Inhibition Overcomes Multiple Resistance Mechanisms to Selective RAF Inhibitors
Whittaker, S. R., Cowley, G. S., Wagner, S., Luo, F., Root, D. E., & Garraway, L. A. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-15-0136-t · Cited by 75
Emerging insights into resistance to BRAF inhibitors in melanoma
Bucheit, A. D., & Davies, M. A. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.11.013 · Cited by 77
Translating Genomics for Precision Cancer Medicine
Roychowdhury, S., & Chinnaiyan, A. M. (2014) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-090413-025552 · Cited by 75
Genetic Alterations and Personalized Medicine in Melanoma: Progress and Future Prospects
Griewank, K., Scolyer, R. A., Thompson, J. F., Flaherty, K. T., Schadendorf, D., & Murali, R. (2014) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djt435 · Cited by 77
Self-citation
Combining targeted therapy and immune checkpoint inhibitors in the treatment of metastatic melanoma.
Kim, T. S., Amaria, R. N., Spencer, C. N., Reuben, A., Cooper, Z. A., & Wargo, J. A. (2014) · PubMed Central · doi:10.7497/j.issn.2095-3941.2014.04.002 · Cited by 76
Self-citation
Fibroblast Growth Factor Receptor Signaling in Skin Cancers
Czyż, M. (2019) · Cells · doi:10.3390/cells8060540 · Cited by 74
Dynamic single-cell RNA sequencing identifies immunotherapy persister cells following PD-1 blockade
Sehgal, K., Portell, A. J., Ivanova, E. V., Lizotte, P. H., Mahadevan, N. R., Greene, J. R., Vajdi, A., Gurjao, C., Teceno, T. J., Taus, L. J., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci135038 · Cited by 78
HGF/c-MET Axis in Tumor Microenvironment and Metastasis Formation
Spina, A., Pasquale, V. D., Cerulo, G., Cocchiaro, P., Morte, R. D., Avallone, L., & Pavone, L. M. (2015) · Biomedicines · doi:10.3390/biomedicines3010071 · Cited by 75
Crosstalk between cancer cells and blood endothelial and lymphatic endothelial cells in tumour and organ microenvironment
Lee, E., Pandey, N. B., & Popel, A. S. (2015) · Expert Reviews in Molecular Medicine · doi:10.1017/erm.2015.2 · Cited by 75
The potential roles of hepatocyte growth factor (HGF)-MET pathway inhibitors in cancer treatment
Appleman, L. J., Parikh, R. A., Wang, P., Beumer, J. H., & Chu, E. (2014) · OncoTargets and Therapy · doi:10.2147/ott.s40241 · Cited by 75
Diminished WNT → β-catenin → c-MYC signaling is a barrier for malignant progression of BRAFV600E-induced lung tumorsPreprint
Juan, J. M., Muraguchi, T., Iezza, G., Sears, R. C., & McMahon, M. (2014) · Genes & Development · doi:10.1101/gad.233627.113 · Cited by 73
The importance of being CAFs (in cancer resistance to targeted therapies)
Rizzolio, S., Giordano, S., & Corso, S. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-022-02524-w · Cited by 75
Redox signaling in drug-tolerant persister cells as an emerging therapeutic target
Zhang, Z., Tan, Y., Huang, C., & Wei, X. (2023) · EBioMedicine · doi:10.1016/j.ebiom.2023.104483 · Cited by 73
In vitro models of tumor vessels and matrix: Engineering approaches to investigate transport limitations and drug delivery in cancer
Seo, B. R., DelNero, P. F., & Fischbach, C. (2013) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2013.11.011 · Cited by 75
Near complete response to Pembrolizumab in microsatellite-stable metastatic sebaceous carcinoma
Domingo‐Musibay, E., Murugan, P. J., Giubellino, A., Sharma, S., Steinberger, D. J., Yuan, J., Hunt, M. A., Lou, E., & Miller, J. S. (2018) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-018-0357-3 · Cited by 76
JUN dependency in distinct early and late BRAF inhibition adaptation states of melanoma
Titz, B., Lomova, A., Le, A., Hugo, W., Kong, X., ten Hoeve, J., Friedman, M., Shi, H., Moriceau, G., Song, C., et al. (2016) · Cell Discovery · doi:10.1038/celldisc.2016.28 · Cited by 75
Self-citation
Deciphering Immune-Associated Genes to Predict Survival in Clear Cell Renal Cell Cancer
Hu, D., Zhou, M., & Zhu, X. (2019) · BioMed Research International · doi:10.1155/2019/2506843 · Cited by 72
Influence of Tumor Microenvironment and Fibroblast Population Plasticity on Melanoma Growth, Therapy Resistance and Immunoescape
Romano, V., Belviso, I., Venuta, A., Ruocco, M. R., Masone, S., Aliotta, F., Fiume, G., Montagnani, S., Avagliano, A., & Arcucci, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22105283 · Cited by 78
The dioxin receptor has tumor suppressor activity in melanoma growth and metastasis
Contador-Troca, M., Alvarez, A. M., Barrasa, E., Rico-Leo, E. M., Catalina‐Fernández, I., Menacho-Márquez, M., Bustelo, X. R., García-Borrón, J. C., Gómez-Durán, Á., Sáenz‐Santamaría, J., et al. (2013) · Carcinogenesis · doi:10.1093/carcin/bgt248 · Cited by 76
Therapeutically targeting tumor microenvironment–mediated drug resistance in estrogen receptor–positive breast cancer
Shee, K., Yang, W., Hinds, J. W., Hampsch, R. A., Varn, F. S., Traphagen, N. A., Patel, K., Cheng, C., Jenkins, N. P., Kettenbach, A. N., et al. (2018) · The Journal of Experimental Medicine · doi:10.1084/jem.20171818 · Cited by 75
Self-citation
Updates on the hepatocyte growth factor/c-Met axis in hepatocellular carcinoma and its therapeutic implications
Garcia‐Vilas, J. A., & Medina, M. Á. (2018) · World Journal of Gastroenterology · doi:10.3748/wjg.v24.i33.3695 · Cited by 72
Heterotypic clustering of circulating tumor cells and circulating cancer-associated fibroblasts facilitates breast cancer metastasis
Sharma, U., Medina-Saenz, K., Miller, P. C., Troness, B., Spartz, A. K., Sandoval-Leon, A. C., Parke, D. N., Seagroves, T. N., Lippman, M. E., & El‐Ashry, D. (2021) · Breast Cancer Research and Treatment · doi:10.1007/s10549-021-06299-0 · Cited by 72
Ferroptosis and Tumor Drug Resistance: Current Status and Major Challenges
Nie, Z., Chen, M., Gao, Y., Huang, D., Cao, H., Peng, Y., Guo, N., Wang, F., & Zhang, S. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.879317 · Cited by 83
Targeting RAS/RAF/MEK/ERK signaling in metastatic melanoma
Wang, A., & Qi, X. (2013) · IUBMB Life · doi:10.1002/iub.1193 · Cited by 74
HDAC Inhibition Overcomes Acute Resistance to MEK Inhibition in BRAF -Mutant Colorectal Cancer by Downregulation of c-FLIPL
Carson, R., Çeltikçi, B., Fenning, C., Javadi, A., Crawford, N., Pérez–Carbonell, L., Lawler, M., Longley, D. B., Johnston, P. G., & Schaeybroeck, S. V. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2701 · Cited by 71
Ligand-associated ERBB2/3 activation confers acquired resistance to FGFR inhibition in FGFR3-dependent cancer cells
Wang, J., Mikse, O. R., Liao, R. G., Li, Y. Y., Tan, L., Janne, P. A., Gray, N. S., Wong, K., & Hammerman, P. S. (2014) · Oncogene · doi:10.1038/onc.2014.161 · Cited by 70
MET/HGF pathway activation as a paradigm of resistance to targeted therapies
Ko, B., He, T., Gadgeel, S. M., & Halmos, B. (2017) · Annals of Translational Medicine · doi:10.21037/atm.2016.12.09 · Cited by 71
Combined BRAF and HSP90 Inhibition in Patients with Unresectable BRAF V600E-Mutant Melanoma
Eroglu, Z., Chen, Y. A., Gibney, G. T., Weber, J. S., Kudchadkar, R. R., Khushalani, N. I., Markowitz, J., Brohl, A. S., Tetteh, L. F., Ramadan, H., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-0565 · Cited by 74
miR-200 deficiency promotes lung cancer metastasis by activating Notch signaling in cancer-associated fibroblastsPreprint
Xue, B., Chuang, C.-H., Prosser, H. M., Fuziwara, C. S., Chan, C., Sahasrabudhe, N. S., Kühn, M., Wu, Y., Chen, J., Biton, A., et al. (2021) · Genes & Development · doi:10.1101/gad.347344.120 · Cited by 74
CAFs-Derived Exosomal miRNA-130a Confers Cisplatin Resistance of NSCLC Cells Through PUM2-Dependent Packaging
Zhang, T., Zhang, P., & Li, H.-X. (2021) · International Journal of Nanomedicine · doi:10.2147/ijn.s271976 · Cited by 71
Inhibitors of pan-PI3K Signaling Synergize with BRAF or MEK Inhibitors to Prevent BRAF-Mutant Melanoma Cell Growth
Sweetlove, M., Wrightson, E., Kolekar, S., Rewcastle, G. W., Baguley, B. C., Shepherd, P. R., & Jamieson, S. M. F. (2015) · Frontiers in Oncology · doi:10.3389/fonc.2015.00135 · Cited by 71
Ormeloxifene Suppresses Desmoplasia and Enhances Sensitivity of Gemcitabine in Pancreatic Cancer
Khan, S., Ebeling, M. C., Chauhan, N., Thompson, P. A., Gara, R. K., Ganju, A., Yallapu, M. M., Behrman, S. W., Zhao, H., Zafar, N., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-2397 · Cited by 72
A high-content image-based method for quantitatively studying context-dependent cell population dynamics
Garvey, C. M., Spiller, E. R., Lindsay, D., Chiang, C.-T., Choi, N. C., Agus, D. B., Mallick, P., Foo, J., & Mumenthaler, S. M. (2016) · Scientific Reports · doi:10.1038/srep29752 · Cited by 69
Macrocyclic peptide-based inhibition and imaging of hepatocyte growth factor
Sakai, K., Passioura, T., Sato, H., Ito, K., Furuhashi, H., Umitsu, M., Takagi, J., Kato, Y., Mukai, H., Warashina, S., et al. (2019) · Nature Chemical Biology · doi:10.1038/s41589-019-0285-7 · Cited by 71
Thirty Years of Research on Met Receptor to Move a Biomarker from Bench to Bedside
Furlan, A., Kherrouche, Z., Montagne, R., Copin, M., & Tulasne, D. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-1932 · Cited by 70
Phase II randomised discontinuation trial of the MET/VEGF receptor inhibitor cabozantinib in metastatic melanoma
DAUD, A. I., Kluger, H. M., Kurzrock, R., Schimmöller, F., Weitzman, A., Samuel, T. A., Moussa, A. H., Gordon, M. S., & Shapiro, G. I. (2017) · British Journal of Cancer · doi:10.1038/bjc.2016.419 · Cited by 70
Targeting the tumour immune microenvironment for cancer therapy in human gastrointestinal malignancies
Zhang, Y., Jiang, X., Zhang, N., Chen, M., Wang, H., & Zhu, D. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.05.017 · Cited by 69
A Feed-Forward Mechanosignaling Loop Confers Resistance to Therapies Targeting the MAPK Pathway in BRAF-Mutant Melanoma
Girard, C. A. J., Lecacheur, M., Jouira, R. B., Berestjuk, I., Diazzi, S., Prod’homme, V., Mallavialle, A., Larbret, F., Gesson, M., Schaub, S., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-2914 · Cited by 74
Revisiting the role of cancer-associated fibroblasts in tumor microenvironment
Lan, X., Li, W., Zhao, K., Wang, J., Li, S., & Hai, Z. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1582532 · Cited by 75
Toward a Molecular Classification of Colorectal Cancer: The Role of BRAF
Thiel, A., & Ristimaki, A. P. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00281 · Cited by 78
Cancer Stem-like Cells Derived from Chemoresistant Tumors Have a Unique Capacity to Prime Tumorigenic Myeloid Cells
Yamashina, T., Baghdadi, M., Yoneda, A., Kinoshita, I., Suzu, S., Dosaka‐Akita, H., & Jinushi, M. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-2169 · Cited by 70
Fibroblast-derived Neuregulin 1 Promotes Compensatory ErbB3 Receptor Signaling in Mutant BRAF Melanoma
Capparelli, C., Rosenbaum, S. R., Berger, A. C., & Aplin, A. E. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.657270 · Cited by 67
Heterogeneity in Melanoma
Shannan, B., Perego, M., Somasundaram, R., & Herlyn, M. (2015) · Cancer treatment and research · doi:10.1007/978-3-319-22539-5_1 · Cited by 70
Targeting epithelial-mesenchymal transition: Metal organic network nano-complexes for preventing tumor metastasis
Fan, J., Zheng, D., Rong, L., Zhu, J., Hong, S., Li, C., Xu, Z., Cheng, S., & Zhang, X. (2017) · Biomaterials · doi:10.1016/j.biomaterials.2017.06.007 · Cited by 70
Intercellular Resistance to BRAF Inhibition Can Be Mediated by Extracellular Vesicle–Associated PDGFRβ
Vella, L. J., Behren, A., Coleman, B. M., Greening, D. W., Hill, A. F., & Cebon, J. S. (2017) · Neoplasia · doi:10.1016/j.neo.2017.07.002 · Cited by 70

Authors: Straussman, R., Morikawa, T., Shee, K., Barzily-Rokni, M., Qian, Z. R., Du, J., Davis, A., Mongare, M. M., Gould, J., Frederick, D. T., Cooper, Z. A., Chapman, P. B., Solit, D. B., Ribas, A., Lo, R. S., Flaherty, K. T., Ogino, S., Wargo, J. A., & Golub, T. R.
Affiliations: Broad Institute (US)
Dana-Farber Cancer Institute (US)
Massachusetts General Hospital (US)
Memorial Sloan Kettering Cancer Center (US)
University of California, Los Angeles (US)
Brigham and Women's Hospital (US)
Corresponding author: Golub, Todd R.
ORCID: Straussman, Ravid
Morikawa, Teppei
Shee, Kevin
Barzily-Rokni, Michal
Qian, Zhi Rong
Gould, Joshua
Frederick, Dennie T.
Cooper, Zachary A.
Chapman, Paul B.
Solit, David B.
Ribas, Antoni
Lo, Roger S.
Flaherty, Keith T.
Ogino, Shuji
Wargo, Jennifer A.
Golub, Todd R.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2012-07
Volume: 487
Issue: 7408
Pages: 500-504
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature11183
PMC: PMC3711467
OpenAlex: W2055624262
Semantic Scholar: d51bc0a1730710ad5e74705bff1a2f756c61fc28
Cited by: 1,771
References: 30
Citations by year: 2026: 51 · 2025: 48 · 2024: 68 · 2023: 93 · 2022: 98 · 2021: 102 · 2020: 114 · 2019: 115 · 2018: 138 · 2017: 150 · 2016: 154 · 2015: 172 · 2014: 215 · 2013: 196 · 2012: 53
FWCI: 82.21
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
eScholarship (California Digital Library) (submittedVersion)
Funders: Howard Hughes Medical Institute
National Cancer Institute (R01CA166480, U54CA112962, P50CA093683, UM1CA186709)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
Keywords: RAF inhibitors, vemurafenib, drug resistance, tumor microenvironment, stromal cells, hepatocyte growth factor, MAPK signaling, PI3K/Akt signaling, combination therapy, co-culture model, targeted therapy, non-specific immunity, cancer cell lines, proteomics, immunohistochemistry, immunofluorescence
MeSH terms: Vemurafenib, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Humans, Indoles, Melanoma, Mutation, Prognosis, Sulfonamides, Signal Transduction, Stromal Cells, Hepatocyte Growth Factor, Coculture Techniques, Drug Resistance, Neoplasm, Proto-Oncogene Proteins c-met, Phosphatidylinositol 3-Kinases, Proteomics, Cell Line, Tumor, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Molecular Targeted Therapy, Tumor Microenvironment

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

Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks