Receptor-Driven ERK Pulses Reconfigure MAPK Signaling and Enable Persistence of Drug-Adapted BRAF-Mutant Melanoma Cells
© 2020 The Authors Targeted inhibition of oncogenic pathways can be highly effective in halting the rapid growth of tumors but often leads to the emergence of slowly dividing persister cells, which constitute a reservoir for the selection of drug-resistant clones. In BRAFV600E melanomas, RAF and MEK...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Elsevier BV
2021
|
| Online Access: | https://hdl.handle.net/1721.1/136137 |
| _version_ | 1811092221326262272 |
|---|---|
| author | Gerosa, Luca Chidley, Christopher Fröhlich, Fabian Sanchez, Gabriela Lim, Sang Kyun Muhlich, Jeremy Chen, Jia-Yun Vallabhaneni, Sreeram Baker, Gregory J Schapiro, Denis Atanasova, Mariya I Chylek, Lily A Shi, Tujin Yi, Lian Nicora, Carrie D Claas, Allison Ng, Thomas SC Kohler, Rainer H Lauffenburger, Douglas A Weissleder, Ralph Miller, Miles A Qian, Wei-Jun Wiley, H Steven Sorger, Peter K |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Gerosa, Luca Chidley, Christopher Fröhlich, Fabian Sanchez, Gabriela Lim, Sang Kyun Muhlich, Jeremy Chen, Jia-Yun Vallabhaneni, Sreeram Baker, Gregory J Schapiro, Denis Atanasova, Mariya I Chylek, Lily A Shi, Tujin Yi, Lian Nicora, Carrie D Claas, Allison Ng, Thomas SC Kohler, Rainer H Lauffenburger, Douglas A Weissleder, Ralph Miller, Miles A Qian, Wei-Jun Wiley, H Steven Sorger, Peter K |
| author_sort | Gerosa, Luca |
| collection | MIT |
| description | © 2020 The Authors Targeted inhibition of oncogenic pathways can be highly effective in halting the rapid growth of tumors but often leads to the emergence of slowly dividing persister cells, which constitute a reservoir for the selection of drug-resistant clones. In BRAFV600E melanomas, RAF and MEK inhibitors efficiently block oncogenic signaling, but persister cells emerge. Here, we show that persister cells escape drug-induced cell-cycle arrest via brief, sporadic ERK pulses generated by transmembrane receptors and growth factors operating in an autocrine/paracrine manner. Quantitative proteomics and computational modeling show that ERK pulsing is enabled by rewiring of mitogen-activated protein kinase (MAPK) signaling: from an oncogenic BRAFV600E monomer-driven configuration that is drug sensitive to a receptor-driven configuration that involves Ras-GTP and RAF dimers and is highly resistant to RAF and MEK inhibitors. Altogether, this work shows that pulsatile MAPK activation by factors in the microenvironment generates a persistent population of melanoma cells that rewires MAPK signaling to sustain non-genetic drug resistance. Gerosa et al. show that pulsatile MAPK activation makes it possible for slow-growing drug-resistant persisters to emerge when BRAF-mutant melanoma cells are exposed to RAF and MEK inhibitors at clinically relevant doses. Computational modeling shows that MAPK signaling exists in two configurations, one activated by oncogenic BRAF that is drug sensitive and the other activated by autocrine/paracrine growth factors and transmembrane receptors that is drug resistant. |
| first_indexed | 2024-09-23T15:15:01Z |
| format | Article |
| id | mit-1721.1/136137 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T15:15:01Z |
| publishDate | 2021 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1361372023-12-08T17:29:01Z Receptor-Driven ERK Pulses Reconfigure MAPK Signaling and Enable Persistence of Drug-Adapted BRAF-Mutant Melanoma Cells Gerosa, Luca Chidley, Christopher Fröhlich, Fabian Sanchez, Gabriela Lim, Sang Kyun Muhlich, Jeremy Chen, Jia-Yun Vallabhaneni, Sreeram Baker, Gregory J Schapiro, Denis Atanasova, Mariya I Chylek, Lily A Shi, Tujin Yi, Lian Nicora, Carrie D Claas, Allison Ng, Thomas SC Kohler, Rainer H Lauffenburger, Douglas A Weissleder, Ralph Miller, Miles A Qian, Wei-Jun Wiley, H Steven Sorger, Peter K Massachusetts Institute of Technology. Department of Biological Engineering © 2020 The Authors Targeted inhibition of oncogenic pathways can be highly effective in halting the rapid growth of tumors but often leads to the emergence of slowly dividing persister cells, which constitute a reservoir for the selection of drug-resistant clones. In BRAFV600E melanomas, RAF and MEK inhibitors efficiently block oncogenic signaling, but persister cells emerge. Here, we show that persister cells escape drug-induced cell-cycle arrest via brief, sporadic ERK pulses generated by transmembrane receptors and growth factors operating in an autocrine/paracrine manner. Quantitative proteomics and computational modeling show that ERK pulsing is enabled by rewiring of mitogen-activated protein kinase (MAPK) signaling: from an oncogenic BRAFV600E monomer-driven configuration that is drug sensitive to a receptor-driven configuration that involves Ras-GTP and RAF dimers and is highly resistant to RAF and MEK inhibitors. Altogether, this work shows that pulsatile MAPK activation by factors in the microenvironment generates a persistent population of melanoma cells that rewires MAPK signaling to sustain non-genetic drug resistance. Gerosa et al. show that pulsatile MAPK activation makes it possible for slow-growing drug-resistant persisters to emerge when BRAF-mutant melanoma cells are exposed to RAF and MEK inhibitors at clinically relevant doses. Computational modeling shows that MAPK signaling exists in two configurations, one activated by oncogenic BRAF that is drug sensitive and the other activated by autocrine/paracrine growth factors and transmembrane receptors that is drug resistant. 2021-10-27T20:31:01Z 2021-10-27T20:31:01Z 2020 2021-09-07T17:15:52Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/136137 en 10.1016/J.CELS.2020.10.002 Cell Systems Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Elsevier BV Elsevier |
| spellingShingle | Gerosa, Luca Chidley, Christopher Fröhlich, Fabian Sanchez, Gabriela Lim, Sang Kyun Muhlich, Jeremy Chen, Jia-Yun Vallabhaneni, Sreeram Baker, Gregory J Schapiro, Denis Atanasova, Mariya I Chylek, Lily A Shi, Tujin Yi, Lian Nicora, Carrie D Claas, Allison Ng, Thomas SC Kohler, Rainer H Lauffenburger, Douglas A Weissleder, Ralph Miller, Miles A Qian, Wei-Jun Wiley, H Steven Sorger, Peter K Receptor-Driven ERK Pulses Reconfigure MAPK Signaling and Enable Persistence of Drug-Adapted BRAF-Mutant Melanoma Cells |
| title | Receptor-Driven ERK Pulses Reconfigure MAPK Signaling and Enable Persistence of Drug-Adapted BRAF-Mutant Melanoma Cells |
| title_full | Receptor-Driven ERK Pulses Reconfigure MAPK Signaling and Enable Persistence of Drug-Adapted BRAF-Mutant Melanoma Cells |
| title_fullStr | Receptor-Driven ERK Pulses Reconfigure MAPK Signaling and Enable Persistence of Drug-Adapted BRAF-Mutant Melanoma Cells |
| title_full_unstemmed | Receptor-Driven ERK Pulses Reconfigure MAPK Signaling and Enable Persistence of Drug-Adapted BRAF-Mutant Melanoma Cells |
| title_short | Receptor-Driven ERK Pulses Reconfigure MAPK Signaling and Enable Persistence of Drug-Adapted BRAF-Mutant Melanoma Cells |
| title_sort | receptor driven erk pulses reconfigure mapk signaling and enable persistence of drug adapted braf mutant melanoma cells |
| url | https://hdl.handle.net/1721.1/136137 |
| work_keys_str_mv | AT gerosaluca receptordrivenerkpulsesreconfiguremapksignalingandenablepersistenceofdrugadaptedbrafmutantmelanomacells AT chidleychristopher receptordrivenerkpulsesreconfiguremapksignalingandenablepersistenceofdrugadaptedbrafmutantmelanomacells AT frohlichfabian receptordrivenerkpulsesreconfiguremapksignalingandenablepersistenceofdrugadaptedbrafmutantmelanomacells AT sanchezgabriela receptordrivenerkpulsesreconfiguremapksignalingandenablepersistenceofdrugadaptedbrafmutantmelanomacells AT limsangkyun receptordrivenerkpulsesreconfiguremapksignalingandenablepersistenceofdrugadaptedbrafmutantmelanomacells AT muhlichjeremy receptordrivenerkpulsesreconfiguremapksignalingandenablepersistenceofdrugadaptedbrafmutantmelanomacells AT chenjiayun receptordrivenerkpulsesreconfiguremapksignalingandenablepersistenceofdrugadaptedbrafmutantmelanomacells AT vallabhanenisreeram receptordrivenerkpulsesreconfiguremapksignalingandenablepersistenceofdrugadaptedbrafmutantmelanomacells AT bakergregoryj receptordrivenerkpulsesreconfiguremapksignalingandenablepersistenceofdrugadaptedbrafmutantmelanomacells AT schapirodenis receptordrivenerkpulsesreconfiguremapksignalingandenablepersistenceofdrugadaptedbrafmutantmelanomacells AT atanasovamariyai receptordrivenerkpulsesreconfiguremapksignalingandenablepersistenceofdrugadaptedbrafmutantmelanomacells AT chyleklilya receptordrivenerkpulsesreconfiguremapksignalingandenablepersistenceofdrugadaptedbrafmutantmelanomacells AT shitujin receptordrivenerkpulsesreconfiguremapksignalingandenablepersistenceofdrugadaptedbrafmutantmelanomacells AT yilian receptordrivenerkpulsesreconfiguremapksignalingandenablepersistenceofdrugadaptedbrafmutantmelanomacells AT nicoracarried receptordrivenerkpulsesreconfiguremapksignalingandenablepersistenceofdrugadaptedbrafmutantmelanomacells AT claasallison receptordrivenerkpulsesreconfiguremapksignalingandenablepersistenceofdrugadaptedbrafmutantmelanomacells AT ngthomassc receptordrivenerkpulsesreconfiguremapksignalingandenablepersistenceofdrugadaptedbrafmutantmelanomacells AT kohlerrainerh receptordrivenerkpulsesreconfiguremapksignalingandenablepersistenceofdrugadaptedbrafmutantmelanomacells AT lauffenburgerdouglasa receptordrivenerkpulsesreconfiguremapksignalingandenablepersistenceofdrugadaptedbrafmutantmelanomacells AT weisslederralph receptordrivenerkpulsesreconfiguremapksignalingandenablepersistenceofdrugadaptedbrafmutantmelanomacells AT millermilesa receptordrivenerkpulsesreconfiguremapksignalingandenablepersistenceofdrugadaptedbrafmutantmelanomacells AT qianweijun receptordrivenerkpulsesreconfiguremapksignalingandenablepersistenceofdrugadaptedbrafmutantmelanomacells AT wileyhsteven receptordrivenerkpulsesreconfiguremapksignalingandenablepersistenceofdrugadaptedbrafmutantmelanomacells AT sorgerpeterk receptordrivenerkpulsesreconfiguremapksignalingandenablepersistenceofdrugadaptedbrafmutantmelanomacells |