RAF Suppression Synergizes with MEK Inhibition in KRAS Mutant Cancer Cells
KRAS is the most frequently mutated oncogene in human cancer, yet no therapies are available to treat KRAS mutant cancers. We used two independent reverse genetic approaches to identify components of the RAS-signaling pathways required for growth of KRAS mutant tumors. Small interfering RNA (siRNA)...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2014-09-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124714006172 |
| _version_ | 1828450747987001344 |
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| author | Simona Lamba Mariangela Russo Chong Sun Luca Lazzari Carlotta Cancelliere Wipawadee Grernrum Cor Lieftink Rene Bernards Federica Di Nicolantonio Alberto Bardelli |
| author_facet | Simona Lamba Mariangela Russo Chong Sun Luca Lazzari Carlotta Cancelliere Wipawadee Grernrum Cor Lieftink Rene Bernards Federica Di Nicolantonio Alberto Bardelli |
| author_sort | Simona Lamba |
| collection | DOAJ |
| description | KRAS is the most frequently mutated oncogene in human cancer, yet no therapies are available to treat KRAS mutant cancers. We used two independent reverse genetic approaches to identify components of the RAS-signaling pathways required for growth of KRAS mutant tumors. Small interfering RNA (siRNA) screening of 37 KRAS mutant colorectal cancer cell lines showed that RAF1 suppression was synthetic lethal with MEK inhibition. An unbiased kinome short hairpin RNA (shRNA)-based screen confirmed this synthetic lethal interaction in colorectal as well as in lung cancer cells bearing KRAS mutations. Compounds targeting RAF kinases can reverse resistance to the MEK inhibitor selumetinib. MEK inhibition induces RAS activation and BRAF-RAF1 dimerization and sustains MEK-ERK signaling, which is responsible for intrinsic resistance to selumetinib. Prolonged dual blockade of RAF and MEK leads to persistent ERK suppression and efficiently induces apoptosis. Our data underlie the relevance of developing combinatorial regimens of drugs targeting the RAF-MEK pathway in KRAS mutant tumors. |
| first_indexed | 2024-12-10T23:27:38Z |
| format | Article |
| id | doaj.art-0548cbb6ffd9481ba6a3ccf3fa4e846b |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-10T23:27:38Z |
| publishDate | 2014-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-0548cbb6ffd9481ba6a3ccf3fa4e846b2022-12-22T01:29:30ZengElsevierCell Reports2211-12472014-09-01851475148310.1016/j.celrep.2014.07.033RAF Suppression Synergizes with MEK Inhibition in KRAS Mutant Cancer CellsSimona Lamba0Mariangela Russo1Chong Sun2Luca Lazzari3Carlotta Cancelliere4Wipawadee Grernrum5Cor Lieftink6Rene Bernards7Federica Di Nicolantonio8Alberto Bardelli9Department of Oncology, University of Torino, Str prov 142 Km 3.95, Candiolo, 10060 Torino, ItalyDepartment of Oncology, University of Torino, Str prov 142 Km 3.95, Candiolo, 10060 Torino, ItalyDivision of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 Amsterdam, the NetherlandsDepartment of Oncology, University of Torino, Str prov 142 Km 3.95, Candiolo, 10060 Torino, ItalyCandiolo Cancer Institute–FPO, IRCCS, Str prov 142 Km 3.95, Candiolo, 10060 Torino, ItalyDivision of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 Amsterdam, the NetherlandsDivision of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 Amsterdam, the NetherlandsDivision of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 Amsterdam, the NetherlandsDepartment of Oncology, University of Torino, Str prov 142 Km 3.95, Candiolo, 10060 Torino, ItalyDepartment of Oncology, University of Torino, Str prov 142 Km 3.95, Candiolo, 10060 Torino, ItalyKRAS is the most frequently mutated oncogene in human cancer, yet no therapies are available to treat KRAS mutant cancers. We used two independent reverse genetic approaches to identify components of the RAS-signaling pathways required for growth of KRAS mutant tumors. Small interfering RNA (siRNA) screening of 37 KRAS mutant colorectal cancer cell lines showed that RAF1 suppression was synthetic lethal with MEK inhibition. An unbiased kinome short hairpin RNA (shRNA)-based screen confirmed this synthetic lethal interaction in colorectal as well as in lung cancer cells bearing KRAS mutations. Compounds targeting RAF kinases can reverse resistance to the MEK inhibitor selumetinib. MEK inhibition induces RAS activation and BRAF-RAF1 dimerization and sustains MEK-ERK signaling, which is responsible for intrinsic resistance to selumetinib. Prolonged dual blockade of RAF and MEK leads to persistent ERK suppression and efficiently induces apoptosis. Our data underlie the relevance of developing combinatorial regimens of drugs targeting the RAF-MEK pathway in KRAS mutant tumors.http://www.sciencedirect.com/science/article/pii/S2211124714006172 |
| spellingShingle | Simona Lamba Mariangela Russo Chong Sun Luca Lazzari Carlotta Cancelliere Wipawadee Grernrum Cor Lieftink Rene Bernards Federica Di Nicolantonio Alberto Bardelli RAF Suppression Synergizes with MEK Inhibition in KRAS Mutant Cancer Cells Cell Reports |
| title | RAF Suppression Synergizes with MEK Inhibition in KRAS Mutant Cancer Cells |
| title_full | RAF Suppression Synergizes with MEK Inhibition in KRAS Mutant Cancer Cells |
| title_fullStr | RAF Suppression Synergizes with MEK Inhibition in KRAS Mutant Cancer Cells |
| title_full_unstemmed | RAF Suppression Synergizes with MEK Inhibition in KRAS Mutant Cancer Cells |
| title_short | RAF Suppression Synergizes with MEK Inhibition in KRAS Mutant Cancer Cells |
| title_sort | raf suppression synergizes with mek inhibition in kras mutant cancer cells |
| url | http://www.sciencedirect.com/science/article/pii/S2211124714006172 |
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