Targeting Extracellular Matrix Remodeling Restores BRAF Inhibitor Sensitivity in BRAFi-resistant Melanoma.
Charles Marusak,Varsha Thakur,Yuan Li,Juliano T. Freitas,Patrick M. Zmina,Vijay S. Thakur,Mayland Chang,Ming Gao,Jiufeng Tan,Min Xiao,Yiling Lu,Gordon B. Mills,Keith T. Flaherty,Dennie T. Frederick,Benchun Miao,Ryan J. Sullivan,Tabea Moll,Genevieve M. Boland,Meenhard Herlyn,Gao Zhang,Barbara Bedogni +20 more
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TLDR
Investigation of the role of ECM remodeling by the collagenase, MT1-MMP, in conferring resistance of v-Raf murine sarcoma viral oncogene homolog B1-mutant melanoma to BRAF inhibitor (BRAFi) therapy found it pivotal to an ECM-based signaling pathway that confers resistance to BRAFi therapy.Abstract:
Purpose: The extracellular matrix (ECM) is an intriguing, yet understudied component of therapy resistance. Here, we investigated the role of ECM remodeling by the collagenase, MT1-MMP, in conferring resistance of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutant melanoma to BRAF inhibitor (BRAFi) therapy. Experimental Design: Publicly available RNA-sequencing data and reverse phase protein array were used to determine the relevance of MT1-MMP upregulation in BRAFi-resistant melanoma in patients, patient-derived xenografts, and cell line–derived tumors. Short hairpin RNA (shRNA)-mediated knockdown of MT1-MMP, inhibition via the selective MT1-MMP/MMP2 inhibitor, ND322, or overexpression of MT1-MMP was used to assess the role of MT1-MMP in mediating resistance to BRAFi. Results: MT1-MMP was consistently upregulated in posttreatment tumor samples derived from patients upon disease progression and in melanoma xenografts and cell lines that acquired resistance to BRAFi. shRNA- or ND322-mediated inhibition of MT1-MMP synergized with BRAFi leading to resensitization of resistant cells and tumors to BRAFi. The resistant phenotype depends on the ability of cells to cleave the ECM. Resistant cells seeded in MT1-MMP uncleavable matrixes were resensitized to BRAFi similarly to MT1-MMP inhibition. This is due to the inability of cells to activate integrinβ1 (ITGB1)/FAK signaling, as restoration of ITGB1 activity is sufficient to maintain resistance to BRAFi in the context of MT1-MMP inhibition. Finally, the increase in MT1-MMP in BRAFi-resistant cells is TGFβ dependent, as inhibition of TGFβ receptors I/II dampens MT1-MMP overexpression and restores sensitivity to BRAF inhibition. Conclusions: BRAF inhibition results in a selective pressure toward higher expression of MT1-MMP. MT1-MMP is pivotal to an ECM-based signaling pathway that confers resistance to BRAFi therapy.read more
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Targeting SOX10-deficient cells to reduce the dormant-invasive phenotype state in melanoma
Claudia Capparelli,Timothy J. Purwin,McKenna Glasheen,Signe Caksa,Manoela Tiago,Nicole A. Wilski,Danielle Pomante,Sheera Rosenbaum,Mai Q. Nguyen,Weijia Cai,Janusz Franco-Barraza,Richard Zheng,G. G. Naveen Kumar,Inna Chervoneva,Ayako Shimada,Vito W. Rebecca,Adam E. Snook,Kim HooKim,Xiaowei Xu,Edna Cukierman,Meenhard Herlyn,Andrew E. Aplin +21 more
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Blockade of the pro‐fibrotic reaction mediated by the miR‐143/‐145 cluster enhances the responses to targeted therapy in melanoma
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Vemurafenib Drives Epithelial-to-Mesenchymal Transition Gene Expression in BRAF Inhibitor‒Resistant BRAFV600E/NRASQ61K Melanoma Enhancing Tumor Growth and Metastasis in a Bioluminescent Murine Model.
TL;DR: In this article, the authors employed phenotypic and transcriptomic analysis of isogenic melanoma cells that differ only by NRAS mutational status (BRAFi-sensitive A375-BRAFV600E/NRASQ61 vs. BRAFi-resistant A375 -BRAFIV600e/NRASCQ61K) to show that BRAFi treatment selectively targets BRAF-resistant cells upregulating epithelial-to-mesenchymal transition (EMT) gene expression, paradoxically promoting invasiveness and metastasis in both
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Analysis of the expression and prognostic value of MT1-MMP, β1-integrin and YAP1 in glioma
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References
More filters
Journal ArticleDOI
Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation
Ramin Nazarian,Hubing Shi,Qi Wang,Xiangju Kong,Richard C. Koya,Hane Lee,Zugen Chen,Mi Kyung Lee,Narsis Attar,Hooman Sazegar,Thinle Chodon,Stanley F. Nelson,Grant A. McArthur,Jeffrey A. Sosman,Antoni Ribas,Roger S. Lo +15 more
TL;DR: It is shown that melanomas escape B-RAF(V600E) targeting not through secondary B-RF(V 600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.
Journal ArticleDOI
Mechanism Of Cell Surface Activation Of 72-kDa Type IV Collagenase ISOLATION OF THE ACTIVATED FORM OF THE MEMBRANE METALLOPROTEASE
Alex Y. Strongin,Ivan E. Collier,Gregory A. Bannikov,Barry L. Marmer,Gregory A. Grant,Gregory I. Goldberg +5 more
TL;DR: Activation of 72T4Cl on the cell membrane provides a basic mechanism for spatially regulated extracellular proteolysis and presents a new target for prognosis and treatment of metastatic disease.
Journal ArticleDOI
COT drives resistance to RAF inhibition through MAP kinase pathway reactivation
Cory M. Johannessen,Jesse S. Boehm,So Young Kim,Sapana R. Thomas,Sapana R. Thomas,Leslie Wardwell,Laura A. Johnson,Laura A. Johnson,Caroline Emery,Nicolas Stransky,Alexandria P. Cogdill,Jordi Barretina,Jordi Barretina,Giordano Caponigro,Haley Hieronymus,Haley Hieronymus,Haley Hieronymus,Ryan R. Murray,Kourosh Salehi-Ashtiani,David E. Hill,Marc Vidal,Jean J. Zhao,Xiaoping Yang,Ozan Alkan,Sungjoon Kim,Jennifer L. Harris,Christine D. Wilson,Vic E. Myer,Peter Finan,David E. Root,Thomas M. Roberts,Todd R. Golub,Todd R. Golub,Keith T. Flaherty,Reinhard Dummer,Barbara L. Weber,William R. Sellers,Robert Schlegel,Jennifer A. Wargo,William C. Hahn,William C. Hahn,Levi A. Garraway,Levi A. Garraway +42 more
TL;DR: Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies.
Journal ArticleDOI
MT1-MMP-Deficient Mice Develop Dwarfism, Osteopenia, Arthritis, and Connective Tissue Disease due to Inadequate Collagen Turnover
Kenn Holmbeck,Paolo Bianco,John J. Caterina,Susan Yamada,Mark Kromer,Sergei A. Kuznetsov,Mahesh H. Mankani,Pamela Gehron Robey,A. Robin Poole,Isabelle Pidoux,Jerrold M. Ward,Henning Birkedal-Hansen +11 more
TL;DR: The findings demonstrate the pivotal function of MT1-MMP in connective tissue metabolism, and illustrate that modeling of the soft connective tissues matrix by resident cells is essential for the development and maintenance of the hard tissues of the skeleton.
Journal ArticleDOI
Acquired Resistance to BRAF Inhibitors Mediated by a RAF Kinase Switch in Melanoma Can Be Overcome by Cotargeting MEK and IGF-1R/PI3K
Jessie Villanueva,Adina Vultur,John T. Lee,Rajasekharan Somasundaram,Mizuho Fukunaga-Kalabis,Angela K. Cipolla,Bradley Wubbenhorst,Xiaowei Xu,Phyllis A. Gimotty,Damien Kee,Ademi Santiago-Walker,Richard Letrero,Kurt D'Andrea,Anitha Pushparajan,James Hayden,Kimberly Dahlman Brown,Sylvie Laquerre,Grant A. McArthur,Jeffrey A. Sosman,Katherine L. Nathanson,Meenhard Herlyn +20 more
TL;DR: Increased IGF-1R and pAKT levels in a post-relapse human tumor sample are consistent with a role for IGF- 1R/PI3K-dependent survival in the development of resistance to BRAF inhibitors.