Rationally co-targeting divergent pathways in KRAS wild-type colorectal cancers by CANscript technology reveals tumor dependence on Notch and Erbb2

Abstract KRAS mutation status can distinguish between metastatic colorectal carcinoma (mCRC) patients who may benefit from therapies that target the epidermal growth factor receptor (EGFR), such as cetuximab. However, patients whose tumors harbor mutant KRAS (codons 12/13, 61 and 146) are often excl...

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Autores principales: Nilesh Brijwani, Misti Jain, Muthu Dhandapani, Farrah Zahed, Pragnashree Mukhopadhyay, Manjusha Biswas, Deepak Khatri, Vinod D. Radhakrishna, Biswanath Majumder, Padhma Radhakrishnan, Saravanan Thiyagarajan
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Publicado: Nature Portfolio 2017
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spelling oai:doaj.org-article:b5b8991e965f494584339194df603f2f2021-12-02T15:05:04ZRationally co-targeting divergent pathways in KRAS wild-type colorectal cancers by CANscript technology reveals tumor dependence on Notch and Erbb210.1038/s41598-017-01566-x2045-2322https://doaj.org/article/b5b8991e965f494584339194df603f2f2017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01566-xhttps://doaj.org/toc/2045-2322Abstract KRAS mutation status can distinguish between metastatic colorectal carcinoma (mCRC) patients who may benefit from therapies that target the epidermal growth factor receptor (EGFR), such as cetuximab. However, patients whose tumors harbor mutant KRAS (codons 12/13, 61 and 146) are often excluded from EGFR-targeted regimens, while other patients with wild type KRAS will sometimes respond favorably to these same drugs. These conflicting observations suggest that a more robust approach to individualize therapy may enable greater frequency of positive clinical outcome for mCRC patients. Here, we utilized alive tumor tissues in ex-vivo platform termed CANscript, which preserves the native tumor heterogeneity, in order to interrogate the antitumor effects of EGFR-targeted drugs in mCRC (n = 40). We demonstrated that, irrespective of KRAS status, cetuximab did not induce an antitumor response in a majority of patient tumors. In the subset of non-responsive tumors, data showed that expression levels of EGFR ligands contributed to a mechanism of resistance. Transcriptomic and phosphoproteomic profiling revealed deregulation of multiple pathways, significantly the Notch and Erbb2. Targeting these nodes concurrently resulted in antitumor efficacy in a majority of cetuximab-resistant tumors. These findings highlight the importance of integrating molecular profile and functional testing tools for optimization of alternate strategies in resistant population.Nilesh BrijwaniMisti JainMuthu DhandapaniFarrah ZahedPragnashree MukhopadhyayManjusha BiswasDeepak KhatriVinod D. RadhakrishnaBiswanath MajumderPadhma RadhakrishnanSaravanan ThiyagarajanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Nilesh Brijwani
Misti Jain
Muthu Dhandapani
Farrah Zahed
Pragnashree Mukhopadhyay
Manjusha Biswas
Deepak Khatri
Vinod D. Radhakrishna
Biswanath Majumder
Padhma Radhakrishnan
Saravanan Thiyagarajan
Rationally co-targeting divergent pathways in KRAS wild-type colorectal cancers by CANscript technology reveals tumor dependence on Notch and Erbb2
description Abstract KRAS mutation status can distinguish between metastatic colorectal carcinoma (mCRC) patients who may benefit from therapies that target the epidermal growth factor receptor (EGFR), such as cetuximab. However, patients whose tumors harbor mutant KRAS (codons 12/13, 61 and 146) are often excluded from EGFR-targeted regimens, while other patients with wild type KRAS will sometimes respond favorably to these same drugs. These conflicting observations suggest that a more robust approach to individualize therapy may enable greater frequency of positive clinical outcome for mCRC patients. Here, we utilized alive tumor tissues in ex-vivo platform termed CANscript, which preserves the native tumor heterogeneity, in order to interrogate the antitumor effects of EGFR-targeted drugs in mCRC (n = 40). We demonstrated that, irrespective of KRAS status, cetuximab did not induce an antitumor response in a majority of patient tumors. In the subset of non-responsive tumors, data showed that expression levels of EGFR ligands contributed to a mechanism of resistance. Transcriptomic and phosphoproteomic profiling revealed deregulation of multiple pathways, significantly the Notch and Erbb2. Targeting these nodes concurrently resulted in antitumor efficacy in a majority of cetuximab-resistant tumors. These findings highlight the importance of integrating molecular profile and functional testing tools for optimization of alternate strategies in resistant population.
format article
author Nilesh Brijwani
Misti Jain
Muthu Dhandapani
Farrah Zahed
Pragnashree Mukhopadhyay
Manjusha Biswas
Deepak Khatri
Vinod D. Radhakrishna
Biswanath Majumder
Padhma Radhakrishnan
Saravanan Thiyagarajan
author_facet Nilesh Brijwani
Misti Jain
Muthu Dhandapani
Farrah Zahed
Pragnashree Mukhopadhyay
Manjusha Biswas
Deepak Khatri
Vinod D. Radhakrishna
Biswanath Majumder
Padhma Radhakrishnan
Saravanan Thiyagarajan
author_sort Nilesh Brijwani
title Rationally co-targeting divergent pathways in KRAS wild-type colorectal cancers by CANscript technology reveals tumor dependence on Notch and Erbb2
title_short Rationally co-targeting divergent pathways in KRAS wild-type colorectal cancers by CANscript technology reveals tumor dependence on Notch and Erbb2
title_full Rationally co-targeting divergent pathways in KRAS wild-type colorectal cancers by CANscript technology reveals tumor dependence on Notch and Erbb2
title_fullStr Rationally co-targeting divergent pathways in KRAS wild-type colorectal cancers by CANscript technology reveals tumor dependence on Notch and Erbb2
title_full_unstemmed Rationally co-targeting divergent pathways in KRAS wild-type colorectal cancers by CANscript technology reveals tumor dependence on Notch and Erbb2
title_sort rationally co-targeting divergent pathways in kras wild-type colorectal cancers by canscript technology reveals tumor dependence on notch and erbb2
publisher Nature Portfolio
publishDate 2017
url https://doaj.org/article/b5b8991e965f494584339194df603f2f
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