Validation and Identification of New Targets in cancer and AGEing (VINTAGE)
Novel mediators in lung oncogenesis – David Santamaria (IDEX-Bordeaux/SIRIC-BRIO chair)
David Santamaría received his PhD from Univ. Autónoma of Madrid (Spain) in 1999, under the guidance of Prof. Jorge B. Schwartzman, studying replication fork barriers. He then joined the team of Prof. Ronald A. Laskey, (1999-2003) at the Wellcome/CRC Institute (Cambridge, UK) where he dealt with the initiation of DNA replication and its connection with cell cycle control. He returned to Spain (2003-2016) as a staff scientist in Prof. Mariano Barbacid group (CNIO, Madrid) where he has used mouse genetics to conduct a comprehensive analysis of the Cyclin Dependent Kinase family and to identify putative therapeutic targets in lung adenocarcinoma. In August 2016 he joined the U1218 Unit as a Junior Group Leader of the Institut Européen de Chimie et Biologie (IECB) to continue his research on novel oncogenic pathways and signalling mediators in lung adenocarcinoma.
Lung cancer is the leading cause of cancer-related mortality worldwide, with an average 5-year survival of 15%. LUAD patients are stratified based on driver mutations such as those in K-RAS, EGFR and ALK genes. Among these subtypes, adenocarcinomas positive for K-RAS mutations have worse overall survival due in part to the fact that EGFR and ALK mutant tumors are treated with targeted therapies. Selective inhibitors for the MEK kinases have been tested in K-RAS mutant LUAD although their efficacy is limited due to excessive toxicity. Thus, in spite of being the most frequent subtype, LUAD patients harboring K-RAS activating mutations currently lack specific therapeutic treatments.
We have recently used mouse genetics to identify and functionally validate targets with potential therapeutic value to devise novel strategies for the treatment of K-RAS driven LUAD. By means of the transcriptional profiling of K-RasG12V-driven early hyperplasias we identified the tyrosine kinase receptor Ddr1 as a potential mediator of K-Ras oncogenic properties. Indeed genetic and pharmacological inhibition of Ddr1 blocked tumour development. Moreover, concomitant inhibition of Ddr1 and Notch signalling, a pro-survival mediator of Ddr1, thwarted progression of murine K-RasG12V;p53-null adenocarcinomas. Importantly, this combined treatment induced regression of K-RAS;p53 mutant patient-derived lung orthoxenografts (PDX) with therapeutic efficacy superior to standard chemotherapy. Our data indicate that combined inhibition of DDR1/NOTCH could be an effective therapy for K-RAS mutant LUAD patients (Ambrogio et al, Nat Medicine 22, 270-7, 2016).
In addition, the initiating oncogenic event in almost half of human lung adenocarcinomas is still unknown. This lack of knowledge complicates the development of selective targeted therapies and we are making an effort to identify potential driver events in this patient group. For instance, these tumours harbour a number of alterations without obvious oncogenic function including B-RAF inactivating mutations. Actually, inactivating B-RAF mutants in lung predominate over the activating V600E allele frequently observed in other tumour types. We have recently demonstrated that the activation of an endogenous B-RafD594A kinase inactive isoform triggers lung adenocarcinoma in vivo, indicating that B-RAF inactivating mutations represent novel oncogenic drivers. We plan to continue our research to identify novel oncogenic mediators in those LUAD patients without known driver mutations.
Recent selected publications (2016)
1. Ambrogio, C., Gómez-López, G., Falcone M., Kim, H.G., Byun, S., Crosetto, N., Blasco, R., Sánchez-Céspedes, M., Ren, X., Wang, Z., Ding, K., Hidalgo, M., Serrano, M., Santamaría, D.* and Barbacid, M.* Combined inhibition of DDR1 and Notch signaling is a therapeutic strategy for KRAS-driven lung adenocarcinoma. Nature Medicine 2016 22, 270-7. *Co-corresponding authors.
2. Ambrogio, C., Barbacid, M. and Santamaría, D. In vivo oncogenic conflict triggered by co-existing KRAS and EGFR activating mutations in lung adenocarcinoma. Oncogene 2016 Oct 24. doi: 10.1038/onc.2016.385.
3. Lopez S, Voisset, E, Tisserand, J.C., Mosca, C., Prebet, T., Santamaria, D., Dubreuil, P. and De Sepulveda, P. An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia. Oncotarget 2016 Jun 13. doi: 10.18632/oncotarget.9965.
4. Ambrogio C, Nadal E, Villanueva A, Gómez-López G, Cash TP, Barbacid M, Santamaría D. KRAS-driven lung adenocarcinoma: combined DDR1/Notch inhibition as an effective therapy. ESMO Open 2016 Sep 6;1(5):e000076.