Home | Personas | Mariano Barbacid

Mariano Barbacid


Mariano Barbacid got his Ph.D. in Madrid’s Universidad Complutense (1974) and trained as a postdoctoral fellow at the US National Cancer Institute (1974-78). In 1978, he started his own research group to study the molecular events responsible for the development of human tumours. His work led in 1982, to the isolation of the first human oncogene and the identification of the first mutation associated with the development of human cancer. These findings, also made independently by two other groups, have been seminal to establish the molecular bases of human cancer.

Using chemically induced tumor models, Barbacid also demonstrated that the activating mutation of Ras oncogenes corresponded with the mutational spectra of the initiating chemical carcinogens, thus establishing the molecular bases for epidemiological studies linking carcinogen exposure with certain human cancers.

He is also credited with the isolation of the TRK oncogene from a colon carcinoma. This work led 30 years later to a new paradigm of tumor-agnostic therapies thanks to the development of selective inhibitors by Loxo and Ignyte, two biotech companies. The discovery of the TRK oncogene also led to the identification of the TRK family of tyrosine protein kinase receptors as the functional receptors for the NGF familiy of neurotrophins.

In 1988, he joined Bristol Myers-Squibb where he became Vice President, Oncology Drug Discovery. In this position, he pioneered the development of what we know now as targeted therapies. In 1998, he returned to Madrid to create and direct the Spanish National Cancer Research Center (CNIO) which in less than 10 years became one of the top cancer research centres in the World.

In the late 90’s Barbacid switched his research interest to the regulation of the cell cycle by the CDKs as potential targets for therapeutic intervention in cancer. His systematic ablation of the CDKs led to a redefinition of the way these kinases contribute to the mammalian cell cycle demonstrating that mammalian cells can proliferate with a single CDKs, CDK1, in a fashion similar to simple eukaryots such as yeasts.

In 2011, Barbacid stepped down as CNIO Director to return to his early research interests aimed at identifying novel therapeutic strategies against K-RAS mutant tumors. To this end, the Barbacid group has embarked in a log term project to validate the therapeutic potential of each member of the MAPK and PI3K pathways using genetically engineered mouse models of lung and pancreatic cancer that faithfully reproduce the natural history of the corresponding human tumors. The systemic elimination or inhibition of each of these targets by genetic means has led to two main conclusions. First of all, tampering with either the MAPK or the PI3K pathway leads to the rapid death of the mice due to unacceptable toxicities. However, ablation of RAF1, EGFR and/or CDK4 induces tumor delay as well as regressions without causing unacceptable toxicities due to the maintenance of active MAPK and PI3K pathways. Recently, the Barbacid group has shown that combining RAF1 and EGFR ablation led to complete regression of a subset of advanced Kras/Tp53 driven pancreatic ductal adenocarcinomas.

Barbacid was inducted to the US National Academy of Sciences as a foreign member in 2012 and in 2014, elected Fellow of the Academy of the American Association for Cancer Research. He holds Honorary Degrees from the Universidad Internacional Menendez y Pelayo (1995), University of Cantabria (2011) and University of Barcelona (2014).

His work has been recognized by several domestic and international awards including the Steiner Prize (Bern, 1988), Ipsen Prize (Paris, 1994), Brupbaher Cancer Research Prize (Zurich, 2005), the Medal of Honor of the International Agency for Cancer Research (Lyon, 2007) and the Burkitt Medal (Dublin, 2017). In 2011, he received an Endowed Chair from the AXA Research Fund (Paris). He is one of the few European scientists to receive two Advanced Grants from the European Research Council (2009 and 2015) since their inception in 2008.

To date, he has authored 311 publications, including 232 original research articles in journals with impact factor. Currently, Dr. Barbacid’s Hirsch "h" factor is 114 (Google Scholar) and 107 (Web of Science).


KRAS oncogenes are responsible for the development of at least one fourth of all human tumors including lung and pancreatic adenocarcinomas, two tumors types with some of the worse prognosis. Unfortunately, development of suitable therapies to treat these tumors has remained elusive for the last thirty years and patients are still treated with old chemotherapy drugs. To address this important health issue, we decided to use genetically engineered mouse tumor models that closely recapitulate the natural history of these tumor types in order to deconstruct, by genetic means, oncogenic K-Ras signaling with the ultimate goal to identify molecular targets whose inhibition will result in therapeutic activity against advanced lung and pancreatic tumors. First, we have designed a new generation of mouse tumor models in which we can separate, both temporally and spatially, tumor induction from target inhibition. These new mouse tumor models make use of the yeast frt-FLp(o) recombinase system to induce cancer-driving mutations by inducing genomic recombination within their endogenous KRas and Trp53 cancer genes in either lung neumocytes or in their pancreatic acinar cells. In addition, these mice carry a transgene that encodes the bacterial CreERT2 inducible recombinase driven by the human Ubiquitin promoter which allows its expression in most, if not all, adult cells and tissues. Finally, these strains are used to introduce conditional knock-out or knock-in alleles of those molecular targets whose therapeutic potential we want to validate. Exposure of mice already bearing advanced tumors (as determined by imaging techniques) to a tamoxifen-containing diet results in the activation of inducible CreERT2 recombinase which allows us to systemically ablate expression of the target or express inactive isoforms. This strategy makes it possible not only to evaluate the therapeutic consequences of ablating/inactivating selected targets, but to determine the potentially toxic effects derived from its systemic elimination or inactivation.

We have used this sophisticated experimental strategy to interrogate the therapeutic as well as potentially toxic consequences of ablating or inactivating each of the members of the MAPKinase cascade, including the Raf, Mek and Erk kinases, as well as key effectors of the PI3Kca. pathway including the PI3K p110alpha and mTOR. We have also evaluated additional upstream and downstream signaling elements, such as the EGF Receptor and the Cyclin-dependent kinases (Cdks) responsible for driving the cell cycle. This systematic approach has revealed that most of the K-Ras signaling effectors are not suitable therapeutic targets due to either lack of therapeutic activity, such as Cdk2, Cdk6 A-Raf or B-Raf, or to the induction of unacceptable toxicities such as the Mek1/2 and Erk1/2 kinases, PI3k p110alpha and Cdk1. Therefore, only c-Raf, EGFR and Cdk4 turned to be suitable therapeutic targets, based not only on their anti-tumor properties, but also on the well tolerated toxicities observed upon their systemic ablation/inactivation. In fact, ablation of c-Raf expression in advanced tumors driven by K-Ras/Trp53 mutations led to significant tumor regressions. Importantly, systemic abrogation of c-Raf expression did not inhibit canonical MAPK signaling, hence, resulting in limited toxicities (Sanclemente et al.. Cancer Cell, 33: 217-228, 2018). We are now combining these targets to define more efficacious therapeutic strategies that could be eventually translated to the clinic. As a result of these studies, we have observed that combined ablation of EGFR and c-RAF expression results in complete regression of a significant percentage of PDAC tumors driven by KRas/Trp53 mutations in genetically engineered mice. Again, systemic elimination of these targets induces toxicities that are well-tolerated. Finally, inhibition of EGFR and c-RAF expression effectively blocked tumor progression in nine independent patient-derived xenografts (PDX) carrying KRAS and TP53 mutations (Blasco et al.. Cancer Cell, 35:573-587, 2019). These results should the door to the development of targeted therapies for patients carrying KRAS mutant lung and pancreatic tumors.


M.T. Blasco, C. Navas, G. Martín-Serrano, O. Graña-Castro, C.G. Lechuga, L. Martín-Díaz, M. Djurec, J. Li, L. Morales-Cacho, L. Esteban-Burgos, J. Perales-Patón, E. Bousquet-Mur, E. Castellano, H.K.C. Jacob, L. Cabras, M Musteanu, M. Drosten, S. Ortega, F. Mulero, B. Sainz Jr., N. Dusetti, J. Iovanna, F. Sánchez-Bueno, M. Hidalgo, H. Khiabanian, R. Rabadán, F. Al-Shahrour, C. Guerra and M. Barbacid. (2019). Complete regression of advanced Pancreatic Ductal Adenocarcinomas upon combined inhibition of EGFR and c-RAF. Cancer Cell, 35:573-587.

M. Djurec, O. Graña, A. Lee, K. Troulé, E. Espinet, L. Cabras, C. Navas, M.T. Blasco, L. Martín-Díaz, M. Burdiel, J. Li, Z. Liu, M. Vallespinós, F. Sanchez-Bueno, M.R. Sprick, A. Trumpp4, B. Sainz Jr, F. Al-Shahrour, R. Rabadán, C. Guerra and M. Barbacid. (2018). Saa3 is a key mediator of the pro-tumorigenic properties of cancer associated fibroblasts in pancreatic tumors. Proc. Natl. Acad. Sci. U.S.A., 115:E1147-E1156.

M. Sanclemente, S. Francoz, L. Esteban-Burgos, E. Bousquet-Mur, M. Djurec, PP. Lopez-Casas, M. Hidalgo, C. Guerra, M. Drosten, M. Musteanu and M. Barbacid.. (2018) c-Raf Ablation Induces Regression of Advanced K-Ras/Trp53 Mutant Lung Adenocarcinomas by a Mechanism Independent of MAPK Signaling. Cancer Cell, 33: 217-228.
Commentaries for this article appeared in:
Cancer Cell: F. McCormick: c-Raf in KRas Mutant Cancers: A Moving Target. Cancer Cell, 33: 158-159
Science Translational Medicine: A. Lujambio A new hope for KRAS mutant cancers. Sci Transl. Medicine, 10: eaas8964 http://stm.sciencemag.org/content/10/429/eaas8964.full
This article was also recommended in F1000Prime as being of special significance in its field

L. Simón-Carrasco, O. Graña, M. Salmón, H.K.C. Jacob, A. Gutierrez, G. Jiménez, M. Drosten, and M Barbacid. (2017) Inactivation of Capicua in adult mice causes T cell lymphoblastic lymphoma. Genes & Dev., 31:1456-1468.
This article was recommended in F1000Prime as being of special significance in its field
This article was selected “Paper of the month” by the Spanish Society of Biochemistry and Molecular Biology (SEBBM)

M. Drosten, C. Guerra and M. Barbacid. (2017). Genetically engineered mouse models of K-Ras driven lung and pancreatic tumors: Validation of therapeutic targets. In Additional Perspectives on Ras and Cancer in the 21st Century (ed. L. VanAelst, J. Downward and F. McCormick). Cold Spring Harb Perspect Med. Aug 4. pii: a031542. doi: 10.1101/cshperspect.a031542.

P. Nieto, C. Ambrogio, L. Esteban-Burgos, G. Gómez-López, M.T. Blasco, Z. Yao, R. Marais, N. Rosen, R. Chiarle, D.G. Pisano, M. Barbacid and D. Santamaría. (2017). A Braf kinase-inactive mutant induces lung adenocarcinoma. Nature, 548:239-243.
Commentaries for this article appeared in:
Cancer Discovery: Research Watch, Inactivating BRAF Mutations Modulate RAS–MAPK Signaling, 10.1158/2159-8290.CD-RW2017-153
Nature Reviews Clinical Oncology: Even kinase-inactive BRAF is oncogenic, doi:10.1038/nrclinonc.2017.140

Z. Yao, R. Yaeger, A. Tao, N.M. Torres, M.T. Chang, M. Drosten, H. Zhao, V.S. Rodrik-Outmezguine, F. Cecchi, T. Hembrough, J. Michels, H. Baumert, L. Miles, N.M. Campbell, E. de Stanchina, D.B. Solit, M. Barbacid, B.S. Taylor and N. Rosen. (2017). Tumors with class 3 BRAF mutants are sensitive to the inhibition of activated RAS. Nature, 548:234-238.
Commentaries for this article appeared in:
Cancer Discovery: Research Watch, Inactivating BRAF Mutations Modulate RAS–MAPK Signaling, 10.1158/2159-8290.CD-RW2017-153.
Nature Reviews Clinical Oncology: Even kinase-inactive BRAF is oncogenic, doi:10.1038/nrclinonc.2017.140

M. Drosten, L. Simón-Carrasco, I. Hernández-Porras, M.C.G. Lechuga, M.T. Blasco, H.K. Jacob, S. Fabbiano, N. Potenz, X.R.G. Bustelo, C. Guerra and M. Barbacid. (2017). H-Ras and K-Ras oncoproteins induce different tumor spectra when driven by the same regulatory sequences. Cancer Res., 77: 707-718.

C. Ambrogio, M. Barbacid and D. Santamaría. (2017). In vivo oncogenic conflicto triggered by co-existing KRAS and EGFR activating mutations in lung adenocarcinoma. Oncogene, 36:2309-2318.

C. Ambrogio, G. Gómez-López, M. Falcone, A. Vidal, E. Nadal, N. Crosetto, R.B. Blasco,, P.J. Fernández-Marcos, M. Sánchez-Céspedes, X. Ren, Z. Wang, K. Ding, M. Hidalgo, M. Serrano, A. Villanueva, D. Santamaría and M Barbacid. (2016). Combined inhibition of Ddr1 and Notch signaling as an effective therapeutic strategy for human K-RAS driven lung adenocarcinoma. Nature Medicine, 22:270-277.
Commentaries for this article appeared in:
Cancer Discovery: Research Watch, Vol 6, February 2016