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Combining MEK and SRC inhibitors for treatment of colorectal cancer demonstrate increased efficacy in vitro but not in vivo

Metastatic colorectal cancer (mCRC) is the second leading cause of cancer deaths in the United States. More than 50% of patients with mCRC harbor mutations of the oncogenic driver RAS (KRAS or NRAS). Because directly targeting most mutations of RAS is technically challenging, researchers have concen...

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Autores principales: Fan, Fan, Ghosh, Susmita, Powell, Reid, Roszik, Jason, Park, Yongsun, Sobieski, Mary, Sorokin, Alexey, Stephan, Clifford, Kopetz, Scott, Ellis, Lee M., Bhattacharya, Rajat
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10035898/
https://www.ncbi.nlm.nih.gov/pubmed/36952536
http://dx.doi.org/10.1371/journal.pone.0281063
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author Fan, Fan
Ghosh, Susmita
Powell, Reid
Roszik, Jason
Park, Yongsun
Sobieski, Mary
Sorokin, Alexey
Stephan, Clifford
Kopetz, Scott
Ellis, Lee M.
Bhattacharya, Rajat
author_facet Fan, Fan
Ghosh, Susmita
Powell, Reid
Roszik, Jason
Park, Yongsun
Sobieski, Mary
Sorokin, Alexey
Stephan, Clifford
Kopetz, Scott
Ellis, Lee M.
Bhattacharya, Rajat
author_sort Fan, Fan
collection PubMed
description Metastatic colorectal cancer (mCRC) is the second leading cause of cancer deaths in the United States. More than 50% of patients with mCRC harbor mutations of the oncogenic driver RAS (KRAS or NRAS). Because directly targeting most mutations of RAS is technically challenging, researchers have concentrated on targeting MEK, a downstream mediator of RAS. However, targeting MEK as single-agent therapy is ineffective in patients with mCRC. We hypothesize that combining a MEK inhibitor with other agents can enhance the efficacy of MEK targeting in mCRC. Unbiased high-throughput screening (HTS) was performed to identify drugs that enhance the efficacy of MEK inhibitors. HTS was performed with KRAS-mutated CRC cells using the MEK inhibitor trametinib as a “backbone” and two “clinically ready” compound libraries approved by the U.S. Food and Drug Administration or in clinical trials. HTS demonstrated that the combination of the SRC inhibitor dasatinib and trametinib was synergistic in CRC cells in vitro (MTT and colony formation assays). Analysis of markers for cell proliferation and apoptosis using fluorescence-activated cell sorting, reverse-phase protein array, or Western blotting demonstrated decreased cell proliferation and increased cell death when targeting both SRC and MEK as compared to single agents in multiple CRC cell lines. However, combining dasatinib and trametinib in vivo at doses in mice equivalent to doses used in humans failed to significantly enhance the antitumor activity of trametinib when compared to that of trametinib alone. These results underscore the importance of performing careful preclinical in vivo validation studies using clinically relevant doses as a prerequisite for translating in vitro findings to the clinic.
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spelling pubmed-100358982023-03-24 Combining MEK and SRC inhibitors for treatment of colorectal cancer demonstrate increased efficacy in vitro but not in vivo Fan, Fan Ghosh, Susmita Powell, Reid Roszik, Jason Park, Yongsun Sobieski, Mary Sorokin, Alexey Stephan, Clifford Kopetz, Scott Ellis, Lee M. Bhattacharya, Rajat PLoS One Research Article Metastatic colorectal cancer (mCRC) is the second leading cause of cancer deaths in the United States. More than 50% of patients with mCRC harbor mutations of the oncogenic driver RAS (KRAS or NRAS). Because directly targeting most mutations of RAS is technically challenging, researchers have concentrated on targeting MEK, a downstream mediator of RAS. However, targeting MEK as single-agent therapy is ineffective in patients with mCRC. We hypothesize that combining a MEK inhibitor with other agents can enhance the efficacy of MEK targeting in mCRC. Unbiased high-throughput screening (HTS) was performed to identify drugs that enhance the efficacy of MEK inhibitors. HTS was performed with KRAS-mutated CRC cells using the MEK inhibitor trametinib as a “backbone” and two “clinically ready” compound libraries approved by the U.S. Food and Drug Administration or in clinical trials. HTS demonstrated that the combination of the SRC inhibitor dasatinib and trametinib was synergistic in CRC cells in vitro (MTT and colony formation assays). Analysis of markers for cell proliferation and apoptosis using fluorescence-activated cell sorting, reverse-phase protein array, or Western blotting demonstrated decreased cell proliferation and increased cell death when targeting both SRC and MEK as compared to single agents in multiple CRC cell lines. However, combining dasatinib and trametinib in vivo at doses in mice equivalent to doses used in humans failed to significantly enhance the antitumor activity of trametinib when compared to that of trametinib alone. These results underscore the importance of performing careful preclinical in vivo validation studies using clinically relevant doses as a prerequisite for translating in vitro findings to the clinic. Public Library of Science 2023-03-23 /pmc/articles/PMC10035898/ /pubmed/36952536 http://dx.doi.org/10.1371/journal.pone.0281063 Text en © 2023 Fan et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Fan, Fan
Ghosh, Susmita
Powell, Reid
Roszik, Jason
Park, Yongsun
Sobieski, Mary
Sorokin, Alexey
Stephan, Clifford
Kopetz, Scott
Ellis, Lee M.
Bhattacharya, Rajat
Combining MEK and SRC inhibitors for treatment of colorectal cancer demonstrate increased efficacy in vitro but not in vivo
title Combining MEK and SRC inhibitors for treatment of colorectal cancer demonstrate increased efficacy in vitro but not in vivo
title_full Combining MEK and SRC inhibitors for treatment of colorectal cancer demonstrate increased efficacy in vitro but not in vivo
title_fullStr Combining MEK and SRC inhibitors for treatment of colorectal cancer demonstrate increased efficacy in vitro but not in vivo
title_full_unstemmed Combining MEK and SRC inhibitors for treatment of colorectal cancer demonstrate increased efficacy in vitro but not in vivo
title_short Combining MEK and SRC inhibitors for treatment of colorectal cancer demonstrate increased efficacy in vitro but not in vivo
title_sort combining mek and src inhibitors for treatment of colorectal cancer demonstrate increased efficacy in vitro but not in vivo
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10035898/
https://www.ncbi.nlm.nih.gov/pubmed/36952536
http://dx.doi.org/10.1371/journal.pone.0281063
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