An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer

Adrian Vallejo; Naiara Perurena; Elisabet Guruceaga; Pawel K Mazur; Susana Martinez-Canarias; Carolina Zandueta; Karmele Valencia; Andrea Arricibita; Dana Gwinn; Leanne C Sayles; Chen-Hua Chuang; Laura Guembe; Peter Bailey; David K Chang; Andrew Biankin; Mariano Ponz-Sarvise; Jesper B Andersen; Purvesh Khatri; Aline Bozec; E Alejandro Sweet-Cordero; Julien Sage; Fernando Lecanda; Silve Vicent

doi:10.1038/ncomms14294

An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer

Adrian Vallejo, Naiara Perurena, Elisabet Guruceaga, Pawel K Mazur, Susana Martinez-Canarias, Carolina Zandueta, Karmele Valencia, Andrea Arricibita, Dana Gwinn, Leanne C Sayles, Chen-Hua Chuang, Laura Guembe, Peter Bailey, David K Chang, Andrew Biankin, Mariano Ponz-Sarvise, Jesper B Andersen, Purvesh Khatri, Aline Bozec, E Alejandro Sweet-CorderoJulien Sage, Fernando Lecanda, Silve Vicent

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Abstract

KRAS mutated tumours represent a large fraction of human cancers, but the vast majority remains refractory to current clinical therapies. Thus, a deeper understanding of the molecular mechanisms triggered by KRAS oncogene may yield alternative therapeutic strategies. Here we report the identification of a common transcriptional signature across mutant KRAS cancers of distinct tissue origin that includes the transcription factor FOSL1. High FOSL1 expression identifies mutant KRAS lung and pancreatic cancer patients with the worst survival outcome. Furthermore, FOSL1 genetic inhibition is detrimental to both KRAS-driven tumour types. Mechanistically, FOSL1 links the KRAS oncogene to components of the mitotic machinery, a pathway previously postulated to function orthogonally to oncogenic KRAS. FOSL1 targets include AURKA, whose inhibition impairs viability of mutant KRAS cells. Lastly, combination of AURKA and MEK inhibitors induces a deleterious effect on mutant KRAS cells. Our findings unveil KRAS downstream effectors that provide opportunities to treat KRAS-driven cancers.

Originalsprog	Engelsk
Artikelnummer	14294
Tidsskrift	Nature Communications
Vol/bind	8
Antal sider	14
ISSN	2041-1723
DOI	https://doi.org/10.1038/ncomms14294
Status	Udgivet - 21 feb. 2017

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10.1038/ncomms14294Licens: CC BY

An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancerForlagets udgivne version, 2,62 MBLicens: CC BY

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Vallejo, A., Perurena, N., Guruceaga, E., Mazur, P. K., Martinez-Canarias, S., Zandueta, C., Valencia, K., Arricibita, A., Gwinn, D., Sayles, L. C., Chuang, C-H., Guembe, L., Bailey, P., Chang, D. K., Biankin, A., Ponz-Sarvise, M., Andersen, J. B., Khatri, P., Bozec, A., ... Vicent, S. (2017). An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer. Nature Communications, 8, [14294]. https://doi.org/10.1038/ncomms14294

Vallejo, A, Perurena, N, Guruceaga, E, Mazur, PK, Martinez-Canarias, S, Zandueta, C, Valencia, K, Arricibita, A, Gwinn, D, Sayles, LC, Chuang, C-H, Guembe, L, Bailey, P, Chang, DK, Biankin, A, Ponz-Sarvise, M, Andersen, JB, Khatri, P, Bozec, A, Sweet-Cordero, EA, Sage, J, Lecanda, F & Vicent, S 2017, 'An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer', Nature Communications, bind 8, 14294. https://doi.org/10.1038/ncomms14294

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title = "An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer",

abstract = "KRAS mutated tumours represent a large fraction of human cancers, but the vast majority remains refractory to current clinical therapies. Thus, a deeper understanding of the molecular mechanisms triggered by KRAS oncogene may yield alternative therapeutic strategies. Here we report the identification of a common transcriptional signature across mutant KRAS cancers of distinct tissue origin that includes the transcription factor FOSL1. High FOSL1 expression identifies mutant KRAS lung and pancreatic cancer patients with the worst survival outcome. Furthermore, FOSL1 genetic inhibition is detrimental to both KRAS-driven tumour types. Mechanistically, FOSL1 links the KRAS oncogene to components of the mitotic machinery, a pathway previously postulated to function orthogonally to oncogenic KRAS. FOSL1 targets include AURKA, whose inhibition impairs viability of mutant KRAS cells. Lastly, combination of AURKA and MEK inhibitors induces a deleterious effect on mutant KRAS cells. Our findings unveil KRAS downstream effectors that provide opportunities to treat KRAS-driven cancers.",

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T1 - An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer

AU - Vallejo, Adrian

AU - Perurena, Naiara

AU - Guruceaga, Elisabet

AU - Mazur, Pawel K

AU - Martinez-Canarias, Susana

AU - Zandueta, Carolina

AU - Valencia, Karmele

AU - Arricibita, Andrea

AU - Gwinn, Dana

AU - Sayles, Leanne C

AU - Chuang, Chen-Hua

AU - Guembe, Laura

AU - Bailey, Peter

AU - Chang, David K

AU - Biankin, Andrew

AU - Ponz-Sarvise, Mariano

AU - Andersen, Jesper B

AU - Khatri, Purvesh

AU - Bozec, Aline

AU - Sweet-Cordero, E Alejandro

AU - Sage, Julien

AU - Lecanda, Fernando

AU - Vicent, Silve

PY - 2017/2/21

Y1 - 2017/2/21

N2 - KRAS mutated tumours represent a large fraction of human cancers, but the vast majority remains refractory to current clinical therapies. Thus, a deeper understanding of the molecular mechanisms triggered by KRAS oncogene may yield alternative therapeutic strategies. Here we report the identification of a common transcriptional signature across mutant KRAS cancers of distinct tissue origin that includes the transcription factor FOSL1. High FOSL1 expression identifies mutant KRAS lung and pancreatic cancer patients with the worst survival outcome. Furthermore, FOSL1 genetic inhibition is detrimental to both KRAS-driven tumour types. Mechanistically, FOSL1 links the KRAS oncogene to components of the mitotic machinery, a pathway previously postulated to function orthogonally to oncogenic KRAS. FOSL1 targets include AURKA, whose inhibition impairs viability of mutant KRAS cells. Lastly, combination of AURKA and MEK inhibitors induces a deleterious effect on mutant KRAS cells. Our findings unveil KRAS downstream effectors that provide opportunities to treat KRAS-driven cancers.

AB - KRAS mutated tumours represent a large fraction of human cancers, but the vast majority remains refractory to current clinical therapies. Thus, a deeper understanding of the molecular mechanisms triggered by KRAS oncogene may yield alternative therapeutic strategies. Here we report the identification of a common transcriptional signature across mutant KRAS cancers of distinct tissue origin that includes the transcription factor FOSL1. High FOSL1 expression identifies mutant KRAS lung and pancreatic cancer patients with the worst survival outcome. Furthermore, FOSL1 genetic inhibition is detrimental to both KRAS-driven tumour types. Mechanistically, FOSL1 links the KRAS oncogene to components of the mitotic machinery, a pathway previously postulated to function orthogonally to oncogenic KRAS. FOSL1 targets include AURKA, whose inhibition impairs viability of mutant KRAS cells. Lastly, combination of AURKA and MEK inhibitors induces a deleterious effect on mutant KRAS cells. Our findings unveil KRAS downstream effectors that provide opportunities to treat KRAS-driven cancers.

KW - Journal Article

U2 - 10.1038/ncomms14294

DO - 10.1038/ncomms14294

M3 - Journal article

C2 - 28220783

SN - 2041-1723

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JO - Nature Communications

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An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer

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