Chemotherapy confers a conserved secondary tolerance to EGFR inhibition via AXL-mediated signaling bypass

Abstract Drug resistance remains the major culprit of therapy failure in disseminated cancers. Simultaneous resistance to multiple, chemically different drugs feeds this failure resulting in cancer relapse. Here, we investigate co-resistance signatures shared between antimitotic drugs (AMDs) and inh...

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Autores principales:	Mark Borris D. Aldonza, Roben D. Delos Reyes, Young Seo Kim, Jayoung Ku, Ana Melisa Barsallo, Ji-Young Hong, Sang Kook Lee, Han Suk Ryu, YongKeun Park, Je-Yoel Cho, Yoosik Kim
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6a9ce31adb9b43ee90c928b9bc9e7e9b
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spelling	oai:doaj.org-article:6a9ce31adb9b43ee90c928b9bc9e7e9b2021-12-02T18:02:48ZChemotherapy confers a conserved secondary tolerance to EGFR inhibition via AXL-mediated signaling bypass10.1038/s41598-021-87599-92045-2322https://doaj.org/article/6a9ce31adb9b43ee90c928b9bc9e7e9b2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87599-9https://doaj.org/toc/2045-2322Abstract Drug resistance remains the major culprit of therapy failure in disseminated cancers. Simultaneous resistance to multiple, chemically different drugs feeds this failure resulting in cancer relapse. Here, we investigate co-resistance signatures shared between antimitotic drugs (AMDs) and inhibitors of receptor tyrosine kinases (RTKs) to probe mechanisms of secondary resistance. We map co-resistance ranks in multiple drug pairs and identified a more widespread occurrence of co-resistance to the EGFR-tyrosine kinase inhibitor (TKI) gefitinib in hundreds of cancer cell lines resistant to at least 11 AMDs. By surveying different parameters of genomic alterations, we find that the two RTKs EGFR and AXL displayed similar alteration and expression signatures. Using acquired paclitaxel and epothilone B resistance as first-line AMD failure models, we show that a stable collateral resistance to gefitinib can be relayed by entering a dynamic, drug-tolerant persister state where AXL acts as bypass signal. Delayed AXL degradation rendered this persistence to become stably resistant. We probed this degradation process using a new EGFR-TKI candidate YD and demonstrated that AXL bypass-driven collateral resistance can be suppressed pharmacologically. The findings emphasize that AXL bypass track is employed by chemoresistant cancer cells upon EGFR inhibition to enter a persister state and evolve resistance to EGFR-TKIs.Mark Borris D. AldonzaRoben D. Delos ReyesYoung Seo KimJayoung KuAna Melisa BarsalloJi-Young HongSang Kook LeeHan Suk RyuYongKeun ParkJe-Yoel ChoYoosik KimNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-22 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mark Borris D. Aldonza Roben D. Delos Reyes Young Seo Kim Jayoung Ku Ana Melisa Barsallo Ji-Young Hong Sang Kook Lee Han Suk Ryu YongKeun Park Je-Yoel Cho Yoosik Kim Chemotherapy confers a conserved secondary tolerance to EGFR inhibition via AXL-mediated signaling bypass
description	Abstract Drug resistance remains the major culprit of therapy failure in disseminated cancers. Simultaneous resistance to multiple, chemically different drugs feeds this failure resulting in cancer relapse. Here, we investigate co-resistance signatures shared between antimitotic drugs (AMDs) and inhibitors of receptor tyrosine kinases (RTKs) to probe mechanisms of secondary resistance. We map co-resistance ranks in multiple drug pairs and identified a more widespread occurrence of co-resistance to the EGFR-tyrosine kinase inhibitor (TKI) gefitinib in hundreds of cancer cell lines resistant to at least 11 AMDs. By surveying different parameters of genomic alterations, we find that the two RTKs EGFR and AXL displayed similar alteration and expression signatures. Using acquired paclitaxel and epothilone B resistance as first-line AMD failure models, we show that a stable collateral resistance to gefitinib can be relayed by entering a dynamic, drug-tolerant persister state where AXL acts as bypass signal. Delayed AXL degradation rendered this persistence to become stably resistant. We probed this degradation process using a new EGFR-TKI candidate YD and demonstrated that AXL bypass-driven collateral resistance can be suppressed pharmacologically. The findings emphasize that AXL bypass track is employed by chemoresistant cancer cells upon EGFR inhibition to enter a persister state and evolve resistance to EGFR-TKIs.
format	article
author	Mark Borris D. Aldonza Roben D. Delos Reyes Young Seo Kim Jayoung Ku Ana Melisa Barsallo Ji-Young Hong Sang Kook Lee Han Suk Ryu YongKeun Park Je-Yoel Cho Yoosik Kim
author_facet	Mark Borris D. Aldonza Roben D. Delos Reyes Young Seo Kim Jayoung Ku Ana Melisa Barsallo Ji-Young Hong Sang Kook Lee Han Suk Ryu YongKeun Park Je-Yoel Cho Yoosik Kim
author_sort	Mark Borris D. Aldonza
title	Chemotherapy confers a conserved secondary tolerance to EGFR inhibition via AXL-mediated signaling bypass
title_short	Chemotherapy confers a conserved secondary tolerance to EGFR inhibition via AXL-mediated signaling bypass
title_full	Chemotherapy confers a conserved secondary tolerance to EGFR inhibition via AXL-mediated signaling bypass
title_fullStr	Chemotherapy confers a conserved secondary tolerance to EGFR inhibition via AXL-mediated signaling bypass
title_full_unstemmed	Chemotherapy confers a conserved secondary tolerance to EGFR inhibition via AXL-mediated signaling bypass
title_sort	chemotherapy confers a conserved secondary tolerance to egfr inhibition via axl-mediated signaling bypass
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/6a9ce31adb9b43ee90c928b9bc9e7e9b
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Chemotherapy confers a conserved secondary tolerance to EGFR inhibition via AXL-mediated signaling bypass

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