Cabozantinib and dasatinib synergize to induce tumor regression in non-clear cell renal cell carcinoma

Hui wen Lue; Daniel S. Derrick; Soumya Rao; Ahna Van Gaest; Larry Cheng; Jennifer Podolak; Samantha Lawson; Changhui Xue; Devin Garg; Ralph White; Christopher W. Ryan; Justin M. Drake; Anna Ritz; Laura M. Heiser; George V. Thomas

doi:10.1016/j.xcrm.2021.100267

Cabozantinib and dasatinib synergize to induce tumor regression in non-clear cell renal cell carcinoma

Hui wen Lue, Daniel S. Derrick, Soumya Rao, Ahna Van Gaest, Larry Cheng, Jennifer Podolak, Samantha Lawson, Changhui Xue, Devin Garg, Ralph White, Christopher W. Ryan, Justin M. Drake, Anna Ritz, Laura M. Heiser, George V. Thomas

Pharmacology

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

The lack of effective treatment options for advanced non-clear cell renal cell carcinoma (NCCRCC) is a critical unmet clinical need. Applying a high-throughput drug screen to multiple human kidney cancer cells, we identify the combination of the VEGFR-MET inhibitor cabozantinib and the SRC inhibitor dasatinib acts synergistically in cells to markedly reduce cell viability. Importantly, the combination is well tolerated and causes tumor regression in vivo. Transcriptional and phosphoproteomic profiling reveals that the combination converges to downregulate the MAPK-ERK signaling pathway, a result not predicted by single-agent analysis alone. Correspondingly, the addition of a MEK inhibitor synergizes with either dasatinib or cabozantinib to increase its efficacy. This study, by using approved, clinically relevant drugs, provides the rationale for the design of effective combination treatments in NCCRCC that can be rapidly translated to the clinic.

Original language	English (US)
Article number	100267
Journal	Cell Reports Medicine
Volume	2
Issue number	5
DOIs	https://doi.org/10.1016/j.xcrm.2021.100267
State	Published - May 18 2021

Bibliographical note

Funding Information:
We thank Mandy Burns and Amanda Jones for administrative support, Moya Costello for artwork, the Histopathology Shared Resource for pathology support, the Massively Parallel Sequencing Shared Resource and Integrated Genomics Shared Resource for genomics support, Jeffrey Tyner and Steve Kurtz for help with drug combination validation studies, Gordon Mills for therapeutic insights, and the Oregon Translational Research and Development Institute (OTRADI) for high-throughput drug screening support. This study was supported by NIH grants R01 CA169172, P30 CA069533, and P30 CA069533 13S5 through the OHSU-Knight Cancer Institute, The Hope Foundation (SWOG), OTRADI, Kure It Cancer Research, the OHSU Department of Pathology and Laboratory faculty support (G.V.T.) and in part by NIH grant R21 CA222455 (G.V.T. and L.M.H.). These studies were supported in part by NIH research grants 1U54CA209988 and U54-HG008100 and the Prospect Creek Foundation (L.M.H.). L.C. is supported by the National Institute of General Medical Sciences of the NIH under award number T32 GM008339. J.M.D. is supported by the Department of Defense Prostate Cancer Research Program W81XWH-15-1-0236 and W81XWH-18-1-0542, the Prostate Cancer Foundation Young Investigator Award, and a grant from the New Jersey Health Foundation. H.-W.L. D.S.D. S.R. A.V.G. J.P. C.X. and S.L. performed the experiments and analyzed the data. D.S.D. and L.M.H. performed the computational analyses. L.C. R.W. III, and J.M.D. performed and analyzed the phosphoproteomics data. A.R. A.V.G. S.R. S.L. and D.G. analyzed the high-throughput screening data. H.-W.L. D.S.D. C.W.R. J.M.D. A.R. L.M.H. and G.V.T. wrote the paper. G.V.T. conceived the project. L.M.H. and G.V.T. supervised all aspects of the work. The authors declare no competing interests.

Funding Information:
We thank Mandy Burns and Amanda Jones for administrative support, Moya Costello for artwork, the Histopathology Shared Resource for pathology support, the Massively Parallel Sequencing Shared Resource and Integrated Genomics Shared Resource for genomics support, Jeffrey Tyner and Steve Kurtz for help with drug combination validation studies, Gordon Mills for therapeutic insights, and the Oregon Translational Research and Development Institute (OTRADI) for high-throughput drug screening support. This study was supported by NIH grants R01 CA169172 , P30 CA069533 , and P30 CA069533 13S5 through the OHSU-Knight Cancer Institute , The Hope Foundation (SWOG) , OTRADI , Kure It Cancer Research , the OHSU Department of Pathology and Laboratory faculty support (G.V.T.) and in part by NIH grant R21 CA222455 (G.V.T. and L.M.H.). These studies were supported in part by NIH research grants 1U54CA209988 and U54-HG008100 and the Prospect Creek Foundation (L.M.H.). L.C. is supported by the National Institute of General Medical Sciences of the NIH under award number T32 GM008339 . J.M.D. is supported by the Department of Defense Prostate Cancer Research Program W81XWH-15-1-0236 and W81XWH-18-1-0542 , the Prostate Cancer Foundation Young Investigator Award , and a grant from the New Jersey Health Foundation .

Publisher Copyright:
© 2021 The Author(s)

Keywords

MEK
SRC
VEGFR
cabozantinib
cobimetinib
combination therapies
dasatinib
high throughput screen
kidney cancer
non-clear cell renal cell carcinoma

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.xcrm.2021.100267

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Lue, H. W., Derrick, D. S., Rao, S., Van Gaest, A., Cheng, L., Podolak, J., Lawson, S., Xue, C., Garg, D., White, R., Ryan, C. W., Drake, J. M., Ritz, A., Heiser, L. M., & Thomas, G. V. (2021). Cabozantinib and dasatinib synergize to induce tumor regression in non-clear cell renal cell carcinoma. Cell Reports Medicine, 2(5), Article 100267. https://doi.org/10.1016/j.xcrm.2021.100267

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abstract = "The lack of effective treatment options for advanced non-clear cell renal cell carcinoma (NCCRCC) is a critical unmet clinical need. Applying a high-throughput drug screen to multiple human kidney cancer cells, we identify the combination of the VEGFR-MET inhibitor cabozantinib and the SRC inhibitor dasatinib acts synergistically in cells to markedly reduce cell viability. Importantly, the combination is well tolerated and causes tumor regression in vivo. Transcriptional and phosphoproteomic profiling reveals that the combination converges to downregulate the MAPK-ERK signaling pathway, a result not predicted by single-agent analysis alone. Correspondingly, the addition of a MEK inhibitor synergizes with either dasatinib or cabozantinib to increase its efficacy. This study, by using approved, clinically relevant drugs, provides the rationale for the design of effective combination treatments in NCCRCC that can be rapidly translated to the clinic.",

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author = "Lue, {Hui wen} and Derrick, {Daniel S.} and Soumya Rao and {Van Gaest}, Ahna and Larry Cheng and Jennifer Podolak and Samantha Lawson and Changhui Xue and Devin Garg and Ralph White and Ryan, {Christopher W.} and Drake, {Justin M.} and Anna Ritz and Heiser, {Laura M.} and Thomas, {George V.}",

note = "Funding Information: We thank Mandy Burns and Amanda Jones for administrative support, Moya Costello for artwork, the Histopathology Shared Resource for pathology support, the Massively Parallel Sequencing Shared Resource and Integrated Genomics Shared Resource for genomics support, Jeffrey Tyner and Steve Kurtz for help with drug combination validation studies, Gordon Mills for therapeutic insights, and the Oregon Translational Research and Development Institute (OTRADI) for high-throughput drug screening support. This study was supported by NIH grants R01 CA169172, P30 CA069533, and P30 CA069533 13S5 through the OHSU-Knight Cancer Institute, The Hope Foundation (SWOG), OTRADI, Kure It Cancer Research, the OHSU Department of Pathology and Laboratory faculty support (G.V.T.) and in part by NIH grant R21 CA222455 (G.V.T. and L.M.H.). These studies were supported in part by NIH research grants 1U54CA209988 and U54-HG008100 and the Prospect Creek Foundation (L.M.H.). L.C. is supported by the National Institute of General Medical Sciences of the NIH under award number T32 GM008339. J.M.D. is supported by the Department of Defense Prostate Cancer Research Program W81XWH-15-1-0236 and W81XWH-18-1-0542, the Prostate Cancer Foundation Young Investigator Award, and a grant from the New Jersey Health Foundation. H.-W.L. D.S.D. S.R. A.V.G. J.P. C.X. and S.L. performed the experiments and analyzed the data. D.S.D. and L.M.H. performed the computational analyses. L.C. R.W. III, and J.M.D. performed and analyzed the phosphoproteomics data. A.R. A.V.G. S.R. S.L. and D.G. analyzed the high-throughput screening data. H.-W.L. D.S.D. C.W.R. J.M.D. A.R. L.M.H. and G.V.T. wrote the paper. G.V.T. conceived the project. L.M.H. and G.V.T. supervised all aspects of the work. The authors declare no competing interests. Funding Information: We thank Mandy Burns and Amanda Jones for administrative support, Moya Costello for artwork, the Histopathology Shared Resource for pathology support, the Massively Parallel Sequencing Shared Resource and Integrated Genomics Shared Resource for genomics support, Jeffrey Tyner and Steve Kurtz for help with drug combination validation studies, Gordon Mills for therapeutic insights, and the Oregon Translational Research and Development Institute (OTRADI) for high-throughput drug screening support. This study was supported by NIH grants R01 CA169172 , P30 CA069533 , and P30 CA069533 13S5 through the OHSU-Knight Cancer Institute , The Hope Foundation (SWOG) , OTRADI , Kure It Cancer Research , the OHSU Department of Pathology and Laboratory faculty support (G.V.T.) and in part by NIH grant R21 CA222455 (G.V.T. and L.M.H.). These studies were supported in part by NIH research grants 1U54CA209988 and U54-HG008100 and the Prospect Creek Foundation (L.M.H.). L.C. is supported by the National Institute of General Medical Sciences of the NIH under award number T32 GM008339 . J.M.D. is supported by the Department of Defense Prostate Cancer Research Program W81XWH-15-1-0236 and W81XWH-18-1-0542 , the Prostate Cancer Foundation Young Investigator Award , and a grant from the New Jersey Health Foundation . Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = may,

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doi = "10.1016/j.xcrm.2021.100267",

language = "English (US)",

volume = "2",

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T1 - Cabozantinib and dasatinib synergize to induce tumor regression in non-clear cell renal cell carcinoma

AU - Lue, Hui wen

AU - Derrick, Daniel S.

AU - Rao, Soumya

AU - Van Gaest, Ahna

AU - Cheng, Larry

AU - Podolak, Jennifer

AU - Lawson, Samantha

AU - Xue, Changhui

AU - Garg, Devin

AU - White, Ralph

AU - Ryan, Christopher W.

AU - Drake, Justin M.

AU - Ritz, Anna

AU - Heiser, Laura M.

AU - Thomas, George V.

N1 - Funding Information: We thank Mandy Burns and Amanda Jones for administrative support, Moya Costello for artwork, the Histopathology Shared Resource for pathology support, the Massively Parallel Sequencing Shared Resource and Integrated Genomics Shared Resource for genomics support, Jeffrey Tyner and Steve Kurtz for help with drug combination validation studies, Gordon Mills for therapeutic insights, and the Oregon Translational Research and Development Institute (OTRADI) for high-throughput drug screening support. This study was supported by NIH grants R01 CA169172, P30 CA069533, and P30 CA069533 13S5 through the OHSU-Knight Cancer Institute, The Hope Foundation (SWOG), OTRADI, Kure It Cancer Research, the OHSU Department of Pathology and Laboratory faculty support (G.V.T.) and in part by NIH grant R21 CA222455 (G.V.T. and L.M.H.). These studies were supported in part by NIH research grants 1U54CA209988 and U54-HG008100 and the Prospect Creek Foundation (L.M.H.). L.C. is supported by the National Institute of General Medical Sciences of the NIH under award number T32 GM008339. J.M.D. is supported by the Department of Defense Prostate Cancer Research Program W81XWH-15-1-0236 and W81XWH-18-1-0542, the Prostate Cancer Foundation Young Investigator Award, and a grant from the New Jersey Health Foundation. H.-W.L. D.S.D. S.R. A.V.G. J.P. C.X. and S.L. performed the experiments and analyzed the data. D.S.D. and L.M.H. performed the computational analyses. L.C. R.W. III, and J.M.D. performed and analyzed the phosphoproteomics data. A.R. A.V.G. S.R. S.L. and D.G. analyzed the high-throughput screening data. H.-W.L. D.S.D. C.W.R. J.M.D. A.R. L.M.H. and G.V.T. wrote the paper. G.V.T. conceived the project. L.M.H. and G.V.T. supervised all aspects of the work. The authors declare no competing interests. Funding Information: We thank Mandy Burns and Amanda Jones for administrative support, Moya Costello for artwork, the Histopathology Shared Resource for pathology support, the Massively Parallel Sequencing Shared Resource and Integrated Genomics Shared Resource for genomics support, Jeffrey Tyner and Steve Kurtz for help with drug combination validation studies, Gordon Mills for therapeutic insights, and the Oregon Translational Research and Development Institute (OTRADI) for high-throughput drug screening support. This study was supported by NIH grants R01 CA169172 , P30 CA069533 , and P30 CA069533 13S5 through the OHSU-Knight Cancer Institute , The Hope Foundation (SWOG) , OTRADI , Kure It Cancer Research , the OHSU Department of Pathology and Laboratory faculty support (G.V.T.) and in part by NIH grant R21 CA222455 (G.V.T. and L.M.H.). These studies were supported in part by NIH research grants 1U54CA209988 and U54-HG008100 and the Prospect Creek Foundation (L.M.H.). L.C. is supported by the National Institute of General Medical Sciences of the NIH under award number T32 GM008339 . J.M.D. is supported by the Department of Defense Prostate Cancer Research Program W81XWH-15-1-0236 and W81XWH-18-1-0542 , the Prostate Cancer Foundation Young Investigator Award , and a grant from the New Jersey Health Foundation . Publisher Copyright: © 2021 The Author(s)

PY - 2021/5/18

Y1 - 2021/5/18

N2 - The lack of effective treatment options for advanced non-clear cell renal cell carcinoma (NCCRCC) is a critical unmet clinical need. Applying a high-throughput drug screen to multiple human kidney cancer cells, we identify the combination of the VEGFR-MET inhibitor cabozantinib and the SRC inhibitor dasatinib acts synergistically in cells to markedly reduce cell viability. Importantly, the combination is well tolerated and causes tumor regression in vivo. Transcriptional and phosphoproteomic profiling reveals that the combination converges to downregulate the MAPK-ERK signaling pathway, a result not predicted by single-agent analysis alone. Correspondingly, the addition of a MEK inhibitor synergizes with either dasatinib or cabozantinib to increase its efficacy. This study, by using approved, clinically relevant drugs, provides the rationale for the design of effective combination treatments in NCCRCC that can be rapidly translated to the clinic.

AB - The lack of effective treatment options for advanced non-clear cell renal cell carcinoma (NCCRCC) is a critical unmet clinical need. Applying a high-throughput drug screen to multiple human kidney cancer cells, we identify the combination of the VEGFR-MET inhibitor cabozantinib and the SRC inhibitor dasatinib acts synergistically in cells to markedly reduce cell viability. Importantly, the combination is well tolerated and causes tumor regression in vivo. Transcriptional and phosphoproteomic profiling reveals that the combination converges to downregulate the MAPK-ERK signaling pathway, a result not predicted by single-agent analysis alone. Correspondingly, the addition of a MEK inhibitor synergizes with either dasatinib or cabozantinib to increase its efficacy. This study, by using approved, clinically relevant drugs, provides the rationale for the design of effective combination treatments in NCCRCC that can be rapidly translated to the clinic.

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KW - SRC

KW - VEGFR

KW - cabozantinib

KW - cobimetinib

KW - combination therapies

KW - dasatinib

KW - high throughput screen

KW - kidney cancer

KW - non-clear cell renal cell carcinoma

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ER -

Cabozantinib and dasatinib synergize to induce tumor regression in non-clear cell renal cell carcinoma

Abstract

Bibliographical note

Keywords

UN SDGs

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