A. Malpica, Grading ovarian serous carcinoma using a two-tier system, Am. J. Surg. Pathol, vol.28, pp.496-504, 2004.

R. W. Tothill, Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome, Clin. Cancer Res, vol.14, pp.5198-5208, 2008.

B. Mateescu, miR-141 and miR-200a act on ovarian tumorigenesis by controlling oxidative stress response, Nat. Med, vol.17, pp.1627-1635, 2011.

. Tcga, Integrated genomic analyses of ovarian carcinoma, Nature, vol.474, pp.609-615, 2011.

S. Bentink, Angiogenic mRNA and microRNA gene expression signature predicts a novel subtype of serous ovarian cancer, PLoS ONE, vol.7, p.30269, 2012.

L. Batista, T. Gruosso, and F. Mechta-grigoriou, Ovarian cancer emerging subtypes: role of oxidative stress and fibrosis in tumour development and response to treatment, Int. J. Biochem. Cell Biol, vol.45, pp.1092-1098, 2013.

R. G. Verhaak, Prognostically relevant gene signatures of high-grade serous ovarian carcinoma, J. Clin. Invest, vol.123, pp.517-525, 2013.

G. E. Konecny, Prognostic and therapeutic relevance of molecular subtypes in high-grade serous ovarian cancer, J. Natl Cancer Inst, vol.106, pp.1-8, 2014.

C. L. Barrett, Systematic transcriptome analysis reveals tumor-specific isoforms for ovarian cancer diagnosis and therapy, Proc. Natl Acad. Sci. USA, vol.112, pp.3050-3057, 2015.

D. D. Bowtell, The genesis and evolution of high-grade serous ovarian cancer, Nat. Rev. Cancer, vol.10, pp.803-808, 2010.

M. Chen, A survival analysis comparing women with ovarian low-grade serous carcinoma to those with high-grade histology, Onco Targets Ther, vol.7, pp.1891-1899, 2014.

A. M. Patch, Whole-genome characterization of chemoresistant ovarian cancer, Nature, vol.521, pp.489-494, 2015.

D. B. Solit, BRAF mutation predicts sensitivity to MEK inhibition, Nature, vol.439, pp.358-362, 2006.

R. S. Tuma, Getting around PLX4032: studies turn up unusual mechanisms of resistance to melanoma drug, J. Natl Cancer Inst, vol.103, pp.170-177, 2011.

J. Farley, Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study, Lancet Oncol, vol.14, pp.134-140, 2013.

K. T. Flaherty, Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations, N. Engl. J. Med, vol.367, pp.1694-1703, 2012.

C. M. Johannessen, COT drives resistance to RAF inhibition through MAP kinase pathway reactivation, Nature, vol.468, pp.968-972, 2010.

S. Das, Tpl2/cot signals activate ERK, JNK, and NF-kappaB in a cell-type and stimulus-specific manner, J. Biol. Chem, vol.280, pp.23748-23757, 2005.

M. P. Belich, A. Salmeron, L. H. Johnston, and S. C. Ley, TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105, Nature, vol.397, pp.363-368, 1999.

S. Beinke, NF-kappaB1 p105 negatively regulates TPL-2 MEK kinase activity, Mol. Cell. Biol, vol.23, pp.4739-4752, 2003.

V. Lang, ABIN-2 forms a ternary complex with TPL-2 and NF-kappa B1 p105 and is essential for TPL-2 protein stability, Mol. Cell. Biol, vol.24, pp.5235-5248, 2004.

S. Papoutsopoulou, ABIN-2 is required for optimal activation of Erk MAP kinase in innate immune responses, Nat. Immunol, vol.7, pp.606-615, 2006.

M. J. Stafford, N. A. Morrice, M. W. Peggie, and P. Cohen, Interleukin-1 stimulated activation of the COT catalytic subunit through the phosphorylation of Thr290 and Ser62, FEBS Lett, vol.580, pp.4010-4014, 2006.

M. J. Robinson, S. Beinke, A. Kouroumalis, P. N. Tsichlis, and S. C. Ley, Phosphorylation of TPL-2 on serine 400 is essential for lipopolysaccharide activation of extracellular signal-regulated kinase in macrophages, Mol. Cell. Biol, vol.27, pp.7355-7364, 2007.

K. Roget, IkappaB kinase 2 regulates TPL-2 activation of extracellular signal-regulated kinases 1 and 2 by direct phosphorylation of TPL-2 serine 400, Mol. Cell. Biol, vol.32, pp.4684-4690, 2012.

V. Mieulet, TPL-2-mediated activation of MAPK downstream of TLR4 signaling is coupled to arginine availability, Sci. Signal, vol.3, p.61, 2010.

M. Vougioukalaki, D. C. Kanellis, K. Gkouskou, and A. G. Eliopoulos, Tpl2 kinase signal transduction in inflammation and cancer, Cancer Lett, vol.304, pp.80-89, 2011.

T. Gantke, S. Sriskantharajah, M. Sadowski, and S. C. Ley, IkappaB kinase regulation of the TPL-2/ERK MAPK pathway, Immunol. Rev, vol.246, pp.168-182, 2012.

J. S. Arthur and S. C. Ley, Mitogen-activated protein kinases in innate immunity, Nat. Rev. Immunol, vol.13, pp.679-692, 2013.

R. Ohara, Identification of the cells expressing cot proto-oncogene mRNA, J. Cell Sci, vol.108, pp.97-103, 1995.

A. Alves and C. , Differential gene expression profile reveals overexpression of MAP3K8 in invasive endometrioid carcinoma, Eur. J. Gynaecol. Oncol, vol.27, pp.589-593, 2006.

J. H. Jeong, TPL2/COT/MAP3K8 (TPL2) activation promotes androgen depletion-independent (ADI) prostate cancer growth, PLoS ONE, vol.6, p.16205, 2011.

B. Tunca, Overexpression of CK20, MAP3K8 and EIF5A correlates with poor prognosis in early-onset colorectal cancer patients, J. Cancer Res. Clin. Oncol, vol.139, pp.691-702, 2013.

H. Davies, Mutations of the BRAF gene in human cancer, Nature, vol.417, pp.949-954, 2002.

M. A. Rahman, A. Salajegheh, R. A. Smith, and A. K. Lam, B-Raf mutation: a key player in molecular biology of cancer, Exp. Mol. Pathol, vol.95, pp.336-342, 2013.

J. Miyoshi, T. Higashi, H. Mukai, T. Ohuchi, and T. Kakunaga, Structure and transforming potential of the human cot oncogene encoding a putative protein kinase, Mol. Cell. Biol, vol.11, pp.4088-4096, 1991.

A. M. Clark, S. H. Reynolds, M. Anderson, and J. S. Wiest, Mutational activation of the MAP3K8 protooncogene in lung cancer, Genes. Chromosomes Cancer, vol.41, pp.99-108, 2004.

L. Ding, Genome remodelling in a basal-like breast cancer metastasis and xenograft, Nature, vol.464, pp.999-1005, 2010.

T. Gantke, S. Sriskantharajah, and S. C. Ley, Regulation and function of TPL-2, an IkappaB kinase-regulated MAP kinase kinase kinase, Cell Res, vol.21, pp.131-145, 2011.

T. Popova, Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation, Cancer Res, vol.72, pp.5454-5462, 2012.

S. Domcke, R. Sinha, D. A. Levine, C. Sander, and N. Schultz, Evaluating cell lines as tumour models by comparison of genomic profiles, Nat. Commun, vol.4, p.2126, 2013.

C. M. Beaufort, Ovarian cancer cell line panel (OCCP): clinical importance of in vitro morphological subtypes, PLoS ONE, vol.9, p.103988, 2014.

S. Tanaka, K. Nakamura, N. Takahasi, and T. Suda, Role of RANKL in physiological and pathological bone resorption and therapeutics targeting the RANKL-RANK signaling system, Immunol. Rev, vol.208, pp.30-49, 2005.

N. Kaila, Identification of a novel class of selective Tpl2 kinase inhibitors: 4-Alkylamino, Bioorg. Med. Chem, vol.15, pp.6425-6442, 2007.

H. W. Lee, Tumor progression locus 2 (Tpl2) kinase contributes tumor growth and metastasis of clear cell renal cell carcinoma, Mol. Cancer Res, vol.11, pp.1375-1386, 2013.

K. F. Roby, Development of a syngeneic mouse model for events related to ovarian cancer, Carcinogenesis, vol.21, pp.585-591, 2000.

C. D. Dumitru, TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway, Cell, vol.103, pp.1071-1083, 2000.

A. Salmeron, Activation of MEK-1 and SEK-1 by Tpl-2 protooncoprotein, a novel MAP kinase kinase kinase, EMBO J, vol.15, pp.817-826, 1996.

C. Tsatsanis, C. Patriotis, and P. Tsichlis, Tpl-2 induces IL-2 expression in T-cell lines by triggering multiple signaling pathways that activate NFAT and NF-kappaB, Oncogene, vol.17, pp.2609-2618, 1998.

M. Chiariello, M. J. Marinissen, and J. S. Gutkind, Multiple mitogen-activated protein kinase signaling pathways connect the cot oncoprotein to the c-jun promoter and to cellular transformation, Mol. Cell. Biol, vol.20, pp.1747-1758, 2000.

M. R. Waterfield, M. Zhang, L. P. Norman, and S. C. Sun, NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase, Mol. Cell, vol.11, pp.685-694, 2003.

J. A. Smith, Identification of the first specific inhibitor of p90 ribosomal S6 kinase (RSK) reveals an unexpected role for RSK in cancer cell proliferation, Cancer Res, vol.65, pp.1027-1034, 2005.

U. Doehn, RSK is a principal effector of the RAS-ERK pathway for eliciting a coordinate promotile/invasive gene program and phenotype in epithelial cells, Mol. Cell, vol.35, pp.511-522, 2009.

Y. Romeo, X. Zhang, and P. P. Roux, Regulation and function of the RSK family of protein kinases, Biochem. J, vol.441, pp.553-569, 2012.

M. Cheng, V. Sexl, C. J. Sherr, and M. F. Roussel, Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1), Proc. Natl Acad. Sci. USA, vol.95, pp.1091-1096, 1998.

I. Hunger-glaser, E. P. Salazar, J. Sinnett-smith, and E. Rozengurt, Bombesin, lysophosphatidic acid, and epidermal growth factor rapidly stimulate focal adhesion kinase phosphorylation at Ser-910: requirement for ERK activation, J. Biol. Chem, vol.278, pp.22631-22643, 2003.

M. D. Schaller, Cellular functions of FAK kinases: insight into molecular mechanisms and novel functions, J. Cell Sci, vol.123, pp.1007-1013, 2010.

K. M. Lee, K. W. Lee, A. M. Bode, H. J. Lee, and Z. Dong, Tpl2 is a key mediator of arsenite-induced signal transduction, Cancer Res, vol.69, pp.8043-8049, 2009.

G. Singer, Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma, J. Natl Cancer Inst, vol.95, pp.484-486, 2003.

C. R. Miller, K. E. Oliver, and J. Farley, MEK1/2 inhibitors in the treatment of gynecologic malignancies, Gynecol. Oncol, vol.133, pp.128-137, 2014.

M. D. Topp, Molecular correlates of platinum response in human highgrade serous ovarian cancer patient-derived xenografts, Mol. Oncol, vol.8, pp.656-668, 2014.

M. W. Audeh, Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial, Lancet, vol.376, pp.245-251, 2010.

M. R. Cronan, Defining MAP3 kinases required for MDA-MB-231 cell tumor growth and metastasis, Oncogene, vol.31, pp.3889-3900, 2012.

K. Gkirtzimanaki, TPL2 kinase is a suppressor of lung carcinogenesis, Proc. Natl Acad. Sci. USA, vol.110, pp.1470-1479, 2013.

J. S. Sebolt-leopold and R. Herrera, Targeting the mitogen-activated protein kinase cascade to treat cancer, Nat. Rev. Cancer, vol.4, pp.937-947, 2004.

P. J. Roberts and T. E. Stinchcombe, KRAS mutation: should we test for it, and does it matter?, J. Clin. Oncol, vol.31, pp.1112-1121, 2013.

A. Toullec, Oxidative stress promotes myofibroblast differentiation and tumour spreading, EMBO Mol. Med, vol.2, pp.211-230, 2010.

S. Lefort, Inhibition of autophagy as a new means of improving chemotherapy efficiency in high-LC3B triple-negative breast cancers, Autophagy, vol.10, pp.2122-2142, 2014.

F. Assayag, A. Richardson, R. Leclere, E. Martel, and A. , Nicolas from the experimental pathology platform at the Curie Institute for help and advice. We thank K. Roby and P. Terranova for their kind gift of the MOSEC cell lines, ID8, IC5 and 2C6, and Christine Ho for her participation in characterizing these cell lines. We are grateful to all members of the animal facilities of the Institut Curie for their helpful expertise, especially V. Dangles-Marie and I. Grandjean. V.M. was supported by funding from the Agence Nationale de la Recherche and the Foundation for Medical Research. This work was also supported by a grant from the Institut National du Cancer (INCa) that we would like to thank. FMG's laboratory is labelized by the Ligue Nationale Contre le Cancer (LNCC), the Institut National de la Santé et de la Recherche Médicale (Inserm) and the Institut Curie, Thuleau from the Preclinical investigation laboratory at Curie Institute for expert technical assistance in establishing PDX models. We thank T. Popova and M.H. Stern for defining the BRCAness status of patients from the Curie cohort

F. M. , V. M. , T. G. , C. G. , S. A. et al., participated in the conception and supervised the project, designed the experiments and wrote the manuscript